Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT02701140 |
| Other study ID # |
Not assigned |
| Secondary ID |
|
| Status |
Completed |
| Phase |
Phase 2/Phase 3
|
| First received |
|
| Last updated |
|
| Start date |
June 2016 |
| Est. completion date |
November 2020 |
Study information
| Verified date |
November 2020 |
| Source |
Catholic University of the Sacred Heart |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
The aim of this study is to assess the pleiotropic effects of ticagrelor that could represent
possible mechanisms for its beneficial effects on cardiovascular mortality. We will test
three different hypotheses:
1. Ticagrelor may increase ischemic preconditioning as compared to clopidogrel in patients
with stable coronary disease, showing multivessel coronary artery disease and undergoing
staged PCI.
2. Ticagrelor may improve microvascular perfusion in the myocardium of patients with
multivessel coronary artery disease undergoing staged PCI.
3. Ticagrelor may exert positive effects enhancing the paracrine modulation, migration,
homing and survival of hBMDSC, with a potential impact on the microvascular dysfunction
and on the protective response to ischemia (cellular preconditioning).
Description:
Ticagrelor is a reversibly binding, direct-acting, oral P2Y12 antagonist used for prevention
of atherothrombotic events in patients with acute coronary syndrome. It does not belong to
thienopyridines; it is a carbocyclic nucleoside, representing a "first-in-class"
cyclopentyl-triazolo-pyrimidine.
In 2 phase II studies, dyspnea was noted to occur as a side effect to ticagrelor in a
dose-dependent fashion; and in the PLATO study, there was a 6% absolute excess of dyspnea in
ticagrelor-treated patients compared with patients treated with clopidogrel. In the
ONSET/OFFSET study dyspnea was more commonly associated with ticagrelor therapy in comparison
with clopidogrel and placebo in patients with stable coronary artery disease (38.6%, 9.3%,
and 8.3%, respectively), but was not associated in this study with any adverse change in
cardiac or pulmonary function. This result was confirmed in patients with acute coronary
syndrome.
The mechanisms for this side effect are largely unknown, although early data indicate that
ticagrelor blocks adenosine reuptake through inhibition of ENT-1 by red blood cells, and it
is known that intravenous adenosine infusion can cause transient dyspnea in the absence of
bronchoconstriction. Another mechanism potentially increasing adenosine levels by ticagrelor
consists in adenosine triphosphate (ATP) release from red blood cells. Moreover, comparison
between ticagrelor and adenosine molecules suggests their similarity; Adenosine is a
well-known key endogenous molecule that regulates tissue functions by activating 4
G-protein-coupled adenosine receptors: A1, A2A, A2B, and A3. Adenosine accumulates in the
extracellular space in response to metabolic stress and cell damage; and elevations of
adenosine are found in ischemia, hypoxia, inflammation, and trauma. Adenosine acts as
cytoprotector by its anti-inflammatory, cardioprotective, cerebroprotective, antisclerotic,
and antifibrotic properties, as well as by platelet inhibition and vasodilation.
It was hypothesized that chronic adenosine overload induced by ticagrelor may contribute to
the vascular outcome benefit observed in PLATO, in addition to its inhibitory effect on
platelet activity via P2Y12 receptor blockade. Very recently, ticagrelor has been shown to
increase adenosine-induced physiological responses in human healthy subjects by shifting the
dose-response curve for adenosine-induced coronary blood flow velocity (CBFV) to the left
and, in non-ST-segment elevation acute coronary syndrome patients treated with percutaneous
coronary intervention and receiving a maintenance dose of ticagrelor, coronary blood flow
velocity augments to a greater degree compared with patients on a prasugrel maintenance dose
in response to increasing adenosine concentrations. These effects are also compatible with
adenosine reuptake blockage, another of the purported pleiotropic effects of ticagrelor. The
enhanced ticagrelor-related adenosine bioavailabilty may have beneficial effects through
three interrelated mechanisms.
Activation of preconditioning: Ischemic preconditioning, consisting in episodes of ischemia
as short as 5 minutes, followed by reperfusion, has been showed to protect the heart from a
subsequent longer coronary artery occlusion by markedly reducing the amount of necrosis.
Adenosine plays a key role in triggering ischemic preconditioning. Indeed, stimulation of A1
adenosine receptors triggers a complex pathway including the epsilon isoform of protein
kinase C, the ATP-dependent potassium channels, the mitochondrial permeability transition
pores as well as others, like a paradoxical protective release of oxygen radicals eventually
making cells more resistant to ischemia. In humans, examples of preconditioning are the
preinfarction angina and the angina "warm-up phenomenon". Preconditioning can be reproduced
experimentally by repetitive balloon inflations in the coronary artery that have as principal
consequences less chest pain and ST-segment elevation. Pharmacological preconditioning can be
induced by intravenous or intracoronary administration of adenosine or A1 agonists of
adenosine. In a recent study in rabbits authors observed an anti-infarct effect of
clopidogrel and cangrelor (the intravenous analog of ticagrelor) and that it was not the
result from blockade of platelet aggregation, but rather from activation of the signal
transduction pathway of pre- and postconditioning, involving the reperfusion injury salvage
kinases (RISK) including Akt and ERK as well as adenosine A2B receptors, mitochondrial KATP
channels, and redox signalingi. This cardioprotective effect of cangrelor was confirmed in a
primate model.
Improvement of coronary microvascular dysfunction. Coronary microvascular dysfunction has
been demonstrated to affect the prognosis of patients with acute coronary syndromes: Furber
et al described that Doppler flow velocity parameters in the infarct-related artery are of
prognostic value for long-term cardiac events. Additionally, Takahashi et al. found an
impaired coronary flow reserve velocity (CFVR) in the infarct-related artery to be
significantly associated with increased cardiac event rates at long-term follow-up.
Furthermore, microvascular function has been demonstrated to be altered even in non-ischemic
regions at distance from the infarcted myocardial tissue and van de Hoef et al. have recently
shown that microvascular dysfunction determined in the reference vessel after percutaneous
coronary intervention is associated with a significantly increased long-term cardiac
mortality.
Microvascular dysfunction is likely to occur also in the setting of non ST-elevation acute
coronary syndromes (NSTEMI): Marzilli et al. found that in patients with unstable angina,
episodes of transient myocardial ischemia at rest are associated with a brisk increase in
coronary microvascular resistance and that this increase is prevented by the administration
of antiplatelet drugs.
Finally, microvascular dysfunction may also occur following successful coronary angioplasty:
coronary flow reserve has been shown to be impaired in the vascular bed subtended by the
treated artery and requires up to three months for this microvascular dysfunction to resolve.
Activation of cellular preconditioning. Human bone marrow derived stem (hBMDSC) have been
shown to have remarkable therapeutic potential in vitro and in vivo. The mechanism of the
therapeutic benefits must be multifaceted, involves enhanced expression, and release of
trophic/growth factors that provide autocrine and paracrine modulation and protection on the
adult human myocardium and stimulation of the endogenous regenerative responses. However,
when this class of cells are exposed into an ischemic environment, revealed reduced survival
rates and impaired angiogenic capacity. Exposure to sub-lethal hypoxia might impair the
intracellular signaling pathways involved in regenerative processes and may not provide a
resource of several trophic agents and growth factors that might play important role in cell
survival, angiogenesis, and differentiation of hBMDSC. Recently, in animal model of
myocardial infarction, P2Y12 blocker cangrelor was shown to be a potent cardioprotective
modulator through mobilization of progenitor cells and protective signaling on myocytes and
smooth muscle cells rather than any effect on platelet aggregation.
STUDY DESIGN AND METHODOLOGY Hypothesis
The aim of this study is to assess the pleiotropic effects of ticagrelor that could represent
possible mechanisms for its beneficial effects on cardiovascular mortality. We will test
three different hypotheses:
1. Ticagrelor may increase ischemic preconditioning as compared to clopidogrel in patients
with stable coronary disease, showing multivessel coronary artery disease and undergoing
staged PCI.
2. Ticagrelor may improve microvascular perfusion in the myocardium of patients with
multivessel coronary artery disease undergoing staged PCI.
3. Ticagrelor may exert positive effects enhancing the paracrine modulation, migration,
homing and survival of hBMDSC, with a potential impact on the microvascular dysfunction
and on the protective response to ischemia (cellular preconditioning).
Study design: The study is a prospective, randomized, open-label, blinded end-point trial
that will enroll patients with multivessel, stable coronary artery disease undergoing
ischemia-related PCI (evaluated by stress test and/or FFR during coronary catheterization),
and requiring staged PCI. Patients that experience an acute coronary syndrome in multivessel
coronary artery disease, and that need to complete the revascularization in the non-culprit
vessel, may be considered stabilized after one month from the culprit vessel PCI, and
therefore may be enrolled. After the procedure the patients should be treated according to
local routines. Randomization will be blocked within each study site, in order to get an even
balance of patients randomized to either drug within each recruiting center.
The recruitment to the present study will be proposed to 66 consecutive patients and will be
submitted for the approval of the local ethics committee and national regulatory authority
(AIFA) and will be carried out according to the Italian regulatory rules.
The study will be conducted according to the protocol and in strict compliance with ICH GCP,
the Declaration of Helsinki and all applicable regulatory requirements. Before the start of
the study, the study protocol, the investigator brochure and other applicable documents will
be submitted to independent Ethics Committees (EC) and responsible national and local
authorities, as required by each participating country's regulations. The study can start
only after the favourable opinion of the EC of the Coordinating Centre. The Coordinating
Centre will inform the investigators in writing that all ethical and legal requirements have
been met before the first patient is enrolled in the study. After the protocol has been
accepted, substantial amendments to this protocol require the approval by the Coordinating
Centre. After the end of the study, a final study report will be prepared and distributed to
regulatory authorities and ECs as required by applicable regulations. Before a patient can
participate in the study, patient's informed consent needs to be obtained according to GCP
and the legal requirements of the country concerned. Patient information sheet and consent
form must have been reviewed and approved by the responsible EC. The investigator or an
authorized designate will explain the nature, purpose, scope and course of the study,
including information on the investigational therapy, potential benefits and risks to the
patient. In addition to oral information, the patient will receive a written patient
information sheet containing all relevant information. Sufficient time will be allowed to
discuss any questions raised. Only after this process is completed, consent for participation
may be given. Consent must be obtained prior to any study specific procedure and with
sufficient time before a study related intervention as per local requirements. The consent
form must be personally signed and dated by the individual giving consent and by the
investigator or designee who lead the informed consent process with the patient. The consent
form must be retained by the investigator as part of the study records. In addition, the
patient will receive a copy of the patient information sheet and a copy of his/her signed and
dated consent form. Confirmation that consent was obtained will also be documented in the
medical records and on the eCRF. Should a protocol amendment be made, the patient information
sheet may need to be revised to reflect the change(s) of the protocol. After the EC has
approved the revised information sheet and consent form, it is the responsibility of the
investigator to inform all active patients affected by the change, and to receive their
written consent for continuation in the study.
All patients must be identifiable throughout the study at the study site. The investigator
will maintain a personal list of patient numbers and patient names for data reconciliation.
Primary Endpoint: 1) comparison of ticagrelor and clopidogrel on delta (difference)
ST-segment elevation by intracoronary ECG during two-step sequential coronary balloon
inflation in the culprit vessel;
Secondary Endpoints: 1) comparison of ticagrelor and clopidogrel on CFR, IMR and FFR measured
in the culprit vessel and reference vessel at the end of PCI. 2) angina score during coronary
balloon inflation.
Statistical analysis and power calculation: Sample size: assuming an absolute difference
(delta) of 4 mm in the change of ST-segment shift from the first to the second balloon
inflation between the 2 groups, we calculated that 30 patients per group will be required to
have an 80% power to detect a statistically significant difference between groups at p <
0.05. Standard deviation (SD) of the primary endpoint is expected to be ~ 5,4 mm in each
treatment group. A total of 66 patients will be enrolled considering a total drop-out rate of
10%.
The main analysis to be made is a comparison of the primary and secondary endpoint
(continuous variables) between the two groups of 30 patients each, that will be evaluated
with Analysis of variance (ANOVA). The co-primary safety endpoint, being a frequency value,
will be analysed using Fisher test.
