Ticagrelor And PrEconditioning in Patients With coronaRy Artery diSease
Condition: Myocardial Ischemia
MeSH terms: Myocardial Ischemia; Ischemia
Study type: Interventional
Phase: Phase 2/Phase 3

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).
    

Detailed 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.
    

Intervention name(s): Coronary stenting; intracoronary ECG recording; Coronary Flow reserve; Index of Microcirculatory Resistance; Fractional Flow Reserve
Intervention type(s): Procedure; Procedure; Procedure; Procedure; Procedure
Intervention description(s): Within 1h after the first PCI, patients will be randomized to either ticagrelor or clopidogrel.; Measurement of ST segment elevation using intracoronary ECG recording; measured with an intracoronary pressure/temperature sensor-tipped guidewire; measured with an intracoronary pressure/temperature sensor-tipped guidewire; measurement of Fractional Flow Reserve during hyperemic phase.
Other intervention name(s): CFR; IMR; FFR
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: PROBE
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary purpose: Treatment