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TITLE PAGE
Pharmacology at work for cardio-oncology:
Ranolazine to treat early cardiotoxicity
induced by antitumor drugs
Giorgio Minotti
CIR and Drug Sciences, University Campus Bio-Medico of Rome, Italy
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Copyright 2013 by the American Society for Pharmacology and Experimental Therapeutics.
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RUNNING TITLE PAGE
RUNNING TITLE: Cancer therapy, cardiotoxicity, and ranolazine
CORRESPONDING AUTHOR ADDRESS:
Giorgio Minotti
CIR and Drug Sciences
University Campus Bio-Medico
Via Alvaro del Portillo, 21
00128 Rome - ITALY
TELEPHONE: 011-39-06-225419109
FAX: 011-39-06-22541456
E-MAIL: [email protected]
NUMBER OF TEXT PAGES : 12
NUMBER OF FIGURES : 3
NUMBER OF REFERENCES : 52
NUMBER OF WORDS Abstract : 234
Body of article: 3981
NONSTANDARD ABBREVIATIONS : HF, heart failure; MI, myocardial infarction; LV, left ventricle;
LVEF, left ventricle ejection fraction; ROS, reactive oxygen species; ACEI, angiotensin converting
enzyme inhibitors; ARB, angiotensin II receptor blockers; INa,Late, late inward sodium current; BNP,
B-type natriuretic peptide; Nt-proBNP, inactive aminoterminal fragment of B-type natriuretic
peptide; Tn, troponin.
RECOMMENDED SECTION ASSIGNMENT : Perspectives in Pharmacology
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ABSTRACT
Antitumor drugs may cause asymptomatic diastolic dysfunction that introduces a lifetime
risk of heart failure or myocardial infarction. Cardio-oncology is the discipline committed to the
cardiac surveillance and management of cancer patients and survivors; however, cardio-oncology
teams do not always attempt to treat early diastolic dysfunction. Common cardiovascular drugs,
such as β blockers or angiotensin converting enzyme inhibitors or others, would be of uncertain
efficacy in diastolic dysfunction. This perspective describes the potential value of ranolazine, an
antianginal drug that improves myocardial perfusion by relieving diastolic wall tension and
dysfunction. Ranolazine acts by inhibiting the late inward sodium current, and pharmacological
reasonings anticipate that antitumor anthracyclines and nonanthracycline chemotherapeutics might
well induce anomalous activation of this current. These notions formed the rationale for a clinical
study of the efficacy and safety of ranolazine in cancer patients. This study was not designed to
demonstrate that ranolazine reduced the lifetime risk of cardiac events; it was designed as a short
term proof-of-concept study that probed the following hypotheses: i) asymptomatic diastolic
dysfunction could be detected few days after patients completed antitumor therapy, ii) ranolazine
was active and safe in relieving echocardiographic and/or biohumoral indices of diastolic
dysfunction, measured at five weeks or six months of ranolazine administration. These facts
illustrate the translational value of pharmacology, which goes from identifying therapeutics
opportunities to validating hypotheses in clinical settings. Pharmacology is a key to the success of
cardio-oncology.
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Introduction
Cardio-oncology is the discipline that cares of the heart of cancer patients; in fact,
conventional chemotherapeutics and some of the newer “targeted” drugs may cause
cardiovascular toxicities that call for preventive or curative measures (Minotti et al, 2010). Cardio-
oncology rests with an in-depth understanding of the mechanisms of cardiotoxicity and a good
collaboration between oncologists and cardiologists. Unfortunately, the mechanisms of toxicity are
only in part understood, and the timing and appropriateness of cardiovascular medications in
cancer patients remain highly debated. Pharmacologists may help cardiologists and oncologists by
providing mechanistic insight and by identifying cardiovascular drugs that proved safe and effective
in patients at risk for cardiotoxicity. This perspective describes how pharmacological reasonings
identified ranolazine as a valuable option and formed the rationale for a proof-of-concept Phase IIB
study with this drug.
General concepts on cardiotoxicity from antitumor drugs
Doxorubicin and other anthracyclines induce both acute and chronic cardiotoxicity. Acute
cardiotoxicity occurs shortly after initiation of an anthracycline regimen and consists of arrhythmias,
hypotension, mild depression of contractile function. Acute cardiotoxicity is relatively infrequent and
usually reversible. In contrast, chronic cardiotoxicity develops in a dose-related manner and
manifests as potentially life-threatening cardiomyopathy and heart failure (HF) (Minotti et al., 2004).
Nonanthracycline chemotherapeutics (alkylators, antimetabolites, tubuline-active agents) may
cause coronary endothelial dysfunction and spasm which manifest as ischemia or arrhythmias, but
the dose-dependence of such events is less obvious. Targeted agents (antibodies, kinase
inhibitors) tend to induce transient cardiac dysfunction, but some of them may render the heart
more vulnerable by anthracyclines. With inhibitors of angiogenesis, cardiotoxicity is aggravated by
class-related effects like microvasculature dysfunction, hypertension, thromboembolism (Kamba
and McDonald, 2007; Schmidinger et al., 2008). Mechanims and manifestations of cardiotoxicity
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from conventional chemotherapeutics or newer drugs have been reviewed elsewhere (Lal et al.,
2013; Menna et al. 2012; Suter et al., 2013).
Cardiotoxicity and the risk:benefit of antitumor drugs
In patients without preexisting cardiovascular risk factors, cumulative doses of 400 mg
doxorubicin/m2 introduce a 5% risk of HF (Swain et al., 2003). Cumulative doses of 240-360 mg of
doxorubicin/m2 cause much lower risk but retain life-saving effects (Gianni et al., 2008). More than
three million Americans are entering their fifth to tenth year of survival since cancer diagnosis, and
many of them received low dose anthracycline regimens (American Cancer Society, 2012).
Nevertheless, studies of breast cancer survivors show that HF may develop five to ten years after
completing chemotherapy (Pinder et al., 2007). Studies of long term childhood cancer survivors
show that >250 mg of anthracycline/m2 was high enough to increase the lifetime risk of HF
(Mulrooney et al., 2009), while 100 mg of anthracycline/m2 was high enough to cause
asymptomatic cardiac dysfunction (Hudson et al., 2007). Survivors of childhood or adult cancer
also show higher incidence of myocardial infarction (MI), which correlates with exposure to
anthracyclines (Minotti et al., 2010). These observations suggest that there is no completely “safe”
dose of anthracyclines in children (Barry et al., 2007) or adults (Menna et al., 2012). In other
studies the risk of delayed MI correlated with patient’s exposure to alkylators like platinum (Altena
et al., 2009) or tubuline-active agents like vincristine (Swerdlow et al., 2007). All such findings
denote that with current treatment protocols, anthracyclines and nonanthacycline
chemotherapetics are life-saving but introduce a lifetime risk of cardiac events.
Antitumor drugs and early diastolic dysfunction
Asymptomatic cancer survivors often present echocardiographic indices of diastolic
dysfunction characterized by altered relaxation or restrictive pattern (stiffness) (Altena et al, 2009;
Carver et al., 2007). In non-oncologic settings, persistent altered relaxation or stiffness cause left
ventricle (LV) remodelling that makes diastolic dysfunction progress to HF with preserved left
ventricle ejection (LVEF) and eventually, to HF with reduced LVEF (Borlaug and Paulus, 2011).
Diastolic dysfunction can also cause and be caused by ischemia. Myocardial stiffness and
remodelling increase interstitial pressure and diminish coronary conductance, eventually inducing
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ischemia that aggravates myocardial stiffness by cytoplasmic Ca2+ overload and other mechanisms
(Hale et al., 2008). In oncologic settings, the progression of cardiotoxicity from asymptomatic
diastolic dysfunction to HF or ischemic disease may be driven by several factors. Cancer survivors
are more susceptible to develop comorbidities that induce or aggravate diastolic dysfunction
(hypertension, diabetes, dyslipidemia) (Armstrong et al., 2012). It follows that asymptomatic
diastolic dysfunction may progress toward HF or ischemic disease by synergizing with risk factors
(“hits”) that matured after completing chemotherapy. Unintentional hits may also come from
targeted therapies or mediastinal irradiation that were administered concomitant with, or after
chemotherapy. The so-called “multiple hits hypothesis of cardiotoxicity” recapitulates such a broad
spectrum of possibilities (Menna et al., 2008).
Unmet needs : Drugs against diastolic dysfunction and proof-of-concept studies
The available evidence suggests that diastolic dysfunction could be detected a few months
after ending chemotherapy (Tassan-Mangina et al., 2006), but the possibility that it developed early
during the course of chemotherapy was not investigated. This calls for proof-of-concept studies
that characterized diastolic dysfunction as the earliest consequence of antitumor therapies and
probed drugs that could safely prevent it.
Dexrazoxane is the only drug approved for preventing anthracycline-related cardiotoxicity.
Dexrazoxane chelates redox-active iron and can also divert topoisomerase IIβ from causing DNA
double-strand breaks associated with altered mitochondrial biogenesis and function. In either case,
dexrazoxane diminished formation of reactive oxygen species (ROS) in the relatively unprotected
heart (Lyu et al., 2007; Menna et al., 2012; Zhang et al., 2012). Clinical use of dexrazoxane has
been limited by unconfirmed reports that it could interfere with anthracycline activity in tumors
(Swain et al., 2007); therefore, current guidelines recommend using dexrazoxane only in patients
who received 300 mg of doxorubicin/m2 and may benefit from continued anthracycline treatment
(Schuchter et al., 2002).
Common cardiovascular drugs (β blockers, angiotensin converting enzyme inhibitors
(ACEI), angiotensin II receptor blockers (ARB), Ca2+ antagonists) prevented chemotherapy-
induced LVEF decreases in some limited studies, but this reflected their ability to reduce heart
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rate-pressure products rather than their ability to prevent an earlier diastolic dysfunction (Menna et
al., 2012). Many doctors also believe that discomforts from chemotherapy (fatigue, nausea,
vomiting) should not be aggravated by discomforts from β blockers, ACEI, ARB, or Ca2+
antagonists (bradicardia, hypotension, cough, fluid retention). There is an unmet need for drugs
that acted on diastolic dysfunction in a specific manner (Paulus and van Ballegoij, 2010).
Ranolazine
The orally available piperazine derivative, ranolazine, was approved by the Food and Drug
Administration as first-line or top-on-therapy agent for the treatment of stable angina; in Europe,
ranolazine was approved for the treatment of stable angina in patients who are inadequately
controlled by, or intolerant to other antianginal drugs (β-blockers, ACEI, ARB, calcium antagonists).
Ranolazine reduces angina episodes, nitrate consumption, uptitration of other antianginal drugs,
and importantly, it does so without reducing heart rate-pressure products (Stone, 2008).
In ischemia-reperfusion or anoxia-reoxygenation, fatty acid oxidation prevails over glucose
oxidation and causes decreased recovery of cardiac energy during reperfusion. Ranolazine was
originally believed to protect the heart by inhibiting fatty acid oxidation and by shifting metabolism
toward glucose oxidation; in preclinical models, however, inhibition of fatty acid oxidation occurred
at concentrations of ranolazine that were much higher than those associated with the beneficial
effects of ranolazine in ischemia/reperfusion or anoxia/reoxygenation (≥100 µM vs ≤20 µM,
respectively) (MacInnes et al., 2003; Matsumura et al., 1998). The preponderance of evidence now
shows that ranolazine acts by inhibiting the late inward sodium current (INa,Late) (Belardinelli et al.,
2006; Hale et al., 2008).
In the repolarizing ischemic LV there is delayed and/or incomplete inactivation of INa,Late.
This causes elevation of intracellular Na+, which exchanges with extracellular Ca2+ via the reverse
mode Na+-Ca2+ exchanger. Excess Ca2+ entry activates myofilaments, increases diastolic wall
tension, and reduces coronary conductance (Hale, 2008). The ischemic heart therefore hosts a
vicious cycle in which ischemia begets ischemia by activating INa,Late and by causing diastolic wall
tension. Ranolazine interrupts this vicious cycle by inhibiting INa,Late (FIGURE 1).
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Ranolazine inhibits INa,Late in a concentration-, voltage-, and frequency- dependent manner,
and it does so with an IC50 value (∼6 µM) that compares well with its therapeutic plasma levels (2-
6 µM). Ranolazine does not inhibit early peak INa (IC50≥300 µM) but it can marginally inhibit the
delayed rectifier K+ current (IKr) or the late inward Ca2+ current (ILate,Ca2+) with IC50 values of 12 or 50
µM, respectively (Antzelevitch et al., 2004; Stone, 2008). The net balance of the effects of
ranolazine on inward depolaring currents (INa,Late, ILate,Ca2+) or outward repolarizing currents (IKr)
translates into modest changes of the action potential duration (approximately 5 to 10 msec
prolongation of corrected QT interval (QTc) in patients treated with 1000 mg ranolazine bid)
(Scirica et al., 2007). Different Na channel isoforms have been characterized and codenamed
Nav1.1 to Nav1.8. The majority of studies identified Nav1.5 as the cardiac channel isoform
associated with INa,Late (Maltsev and Undrovinas, 2008).
In preclinical models, ranolazine improved diastolic relaxation (“positive lusitropic effect”) in
isolated rat hearts exposed to ischemia-reperfusion (Hwang et al., 2009) and in isometrically
contracting ventricular muscle strips from end-stage failing human hearts (Sossalla et al., 2008).
Pharmacologic rationale to probe ranolazine in diastolic dysfunction from antitumor
drugs
In patients with chronic angina, INa,Late is activated by hypoxia, accumulation of ischemic
metabolites, overproduction of ROS and of reactive nitrogen species (Stone, 2008). In patients
treated with anthracyclines, oxygen- and nitrogen- centered reactive species accumulate after
redox activation of anthracyclines in cardiomyocytes and endothelial cells (Minotti et al., 2004). By
continuously forming ROS, anthracyclines can also diminish oxygen tension and set the stage for
cardiac hypoxia and metabolic ischemia (Ganey et al., 1991). Moreover, anthracyclines increase
cytoplasmic Ca2+ by mechanisms that go from an increased sarcoplasmic release of Ca2+ to an
impaired sequestration of Ca2+ in mitochondria or sarcoplasmic reticulum (Minotti et al., 2004).
Anthracycline-induced diastolic dysfunction should be a good target for drugs, like ranolazine, that
inhibited INa,Late and prevented cytoplasmic Ca2+ overload (FIGURE 2A). It was in keeping with this
rationale that ranolazine prevented elevations of LV end diastolic pressure, an index of diastolic
dysfunction, in isolated rat heart perfused with doxorubicin1.
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INa,Late should also be activated by nonanthracycline chemotherapeutics that caused
coronary endothelial dysfunction and ischemia, whether silent or heralded by transient arrhythmias.
One such mechanism of activation would be potentiated if nonanthracycline chemotherapeutics
were combined with anthracyclines that activated INa,Late and caused diastolic dysfunction by their
own mechanisms. Ranolazine inhibition of INa,Late might break reciprocal interactions between
anthracyclines and nonanthracycline chemotherapeutics in multiagent therapies (FIGURE 2B).
Cardiac benefits from ranolazine would be at the cost of minimal discomfort. Dizziness,
nausea, and constipation were seen in patients receiving 1000 or 1500 mg bid in registratory trials
(maximum recommended dose is 1000 mg bid in US or 750 mg bid in Europe). Symptoms may be
more frequent in patients <60 kg body weight, but dose reductions relieve the side effects of
ranolazine without diminishing its efficacy.
Probing ranolazine in diastolic dysfunction from antitumor drugs: bottlenecks and
requirements
To focus on diastolic dysfunction from antitumor drugs, and to probe its preventability or
curability by ranolazine, one should not recruit patients with pre-existing diastolic dysfunction or
any other cardiovascular or metabolic disease that causes or aggravates diastolic dysfunction. The
LVEF must be ≥50%, and QTc values must be in the range of normality. In other words,
inclusion/exclusion criteria should be tailored to recruit patients who showed “normal” at screening,
such that any newly diagnosed diastolic dysfunction could be unambiguously attributed to the
effects of antitumor drugs. These requirements introduce a bottleneck in patients’ recruitment, and
call for powering the study with a sufficient number of participating centers.
Cardiac function should be measured by techniques that are easy-to-perform in the everyday
life of a clinical center and cause little discomfort to cancer patients. Transthoracic
echocardiography is a rapid, well-tolerated, noninvasive technique that measures systolic function
(LVEF) and diastolic parameters such as the peak early filling (E-wave) and late diastolic filling (A-
wave) velocities, the E/A ratio, and the deceleration time (DT) of early filling velocity. E/A and DT
values follow established patterns of alteration in patients with diastolic impaired relaxation or
restriction, which can be graded I to III according to deviations from age-adjusted ranges of
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normality (Nagueh et al., 2009). Operator bias is minimized by having the same cardiologist
perform serial measurements in the same patient. With a due tolerance, E/A ratio and DT can be
measured also in patients with a poor acoustic window, as is the case of breast cancer patients
carrying expanders or prostheses. Tissue Doppler imaging of early diastolic velocity of mitral
annular should be left to operator’s discretion. This technique proved most informative when
operators averaged signals acquired at both septal and lateral sides of the mitral annulus (Nagueh
et al., 2009); unfortunately, this may not always be feasible in aforesaid patients with a poor
acoustic window.
Early diastolic dysfunction may be subtle enough not to be identified by echocardiography.
Biomarkers can help to overcome this problem. When the LV wall tension increases,
cardiomyocytes release a pre-prohormone B-type natriuretic peptide that is cleaved by circulating
endoproteases to release active B-type natriuretic peptide (BNP) and an inactive aminoterminal
fragment of the prohormone (Nt-proBNP) (Braunwald, 2008). These peptides are good markers of
diastolic altered relaxation or stiffness (Mottram and Marwick, 2005). In oncologic settings,
transient post-infusional elevations of BNP or Nt-proBNP might denote fluid overload and LV
stretch rather than cardiac dysfunction; at a distance from chemotherapy infusions, however, high
BNP or Nt-proBNP would denote authentic cardiotoxicity (Sandri et al., 2005). The circulating half-
life of Nt-proBNP is appreciably longer than that of BNP (Braunwald, 2008). Persistent elevations
of Nt-proBNP should be easier to capture and to correlate with early diastolic dysfunction even
before this could be firmly identified by echocardiography.
Troponin (Tn) measurements provide additional information. In blood samples collected
immediately after ending chemotherapy infusions, Tn elevations denote that antitumor drugs
caused necrosis of a definite number of cardiomyocytes. This was shown to precede LVEF
decreases in some patients, particularly if chemotherapy was high dose and killed more
cardiomyocytes than cardiac progenitor cells could replace (Cardinale et al., 2006). At a distance
from chemotherapy infusions, however, Tn elevations should more likely denote persistent
synergism between subthreshold cellular damage from antitumor drugs and subclinical ischemia
from diastolic dysfunction and reduced coronary conductance, with such a synergism causing
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some cardiomyocytes to die. Looking at persistent Tn elevations is therefore advisable if one
suspected that standard dose chemotherapy was priming the heart to diastolic dysfunction.
Regrettably, there is a lack of studies that prospectively assessed elevations of Nt-proBNP and/or
Tn in cancer patients at risk for early diastolic dysfunction. Clinical studies of ranolazine should
incorporate these laboratory surrogates and make correlations between them and
echocardiographic findings.
Further problems may originate from pharmacokinetic interactions between ranolazine
and antitumor drugs. Ranolazine is a substrate and weak inhibitor of cytochrome P450 3A
enzymes; ranolazine is also a substrate for the drug transporter P-glycoprotein, which is common
for drugs that are substrates of cytochrome P450 3A enzymes (Jerling, 2006). Because
metabolisation and elimination of anthracyclines or nonanthracycline chemotherapeutics also
depend on cytochrome P450 3A enzymes and P-glycoprotein (Wilde et al., 2007), concomitant
administration of ranolazine could change patient’s exposure to antitumor drugs. Safety reasons
therefore advise not to administer ranolazine during chemotherapy. In other words, ranolazine
should not be used to prevent diastolic dysfunction; ranolazine should be commenced at the end of
chemotherapy to relieve early diastolic dysfunction. In the light of cause-and-effect relations
between early diastolic dysfunction and late symptomatic events, this approach still incorporates
prevention of delayed cardiotoxicity.
The INTERACT Study
The INTERACT Study (RanolazINe to Treat EaRly CArdiotoxiCity induced by antiTumor
drugs, EUDRA-CT 2009-016930-29) was designed at the Drug Sciences and Clinical
Pharmacology Center of University Campus Bio-Medico of Rome. INTERACT recruits patients with
normal cardiovascular function and no comorbidity, it assesses cardiac function by both
echocardiography and measurements of Nt-pro-BNP and TnI, it introduces ranolazine at an early
post-chemotherapy assessment if a patient presented with LVEF ≥50% but showed
echocardiographic indices of diastolic dysfunction and/or elevations of TnI or Nt-proBNP.
INTERACT was not designed to show that ranolazine could mitigate the lifetime risk of
cardiotoxicity. INTERACT was designed as a short term proof-of-concept study that validated the
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following hypotheses: i) diastolic dysfunction with preserved LVEF can be detected as early as a
patient completed his/her chemotherapy, and ii) ranolazine relieves diastolic dysfunction to the
extent that antitumor drugs activated INa,Late or caused processes that were aggravated by INa,Late.
Essential study design
INTERACT is a multicenter Phase IIB open label study that plans to recruit 100 patients,
aged 18 to 70 years, scheduled to receive standard dose anthracycline-containing multiagent
chemotherapy for the treatment of non-Hodgkin lymphoma or the adjuvant treatment of breast
cancer, or standard dose nonanthracycline multiagent chemotherapy for the adjuvant treatment of
colorectal cancer. The incidence and curability of cardiotoxicity induced by sequential hits
(chemotherapy plus targeted therapy or mediastinal irradiation) is not in the scope of INTERACT.
Therefore, INTERACT does not recruit patients who require post-chemotherapy mediastinal
irradiation nor recruits breast cancer patients who require post-chemotherapy administration of the
anti-epidermal growth factor receptor-2 monoclonal antibody, trastuzumab2.
Patients with non Hodgkin lymphoma will receive a cumulative dose of 300 mg of
doxorubicin/m2. Women with breast cancer will receive 240 mg of doxorubicin/m2 or 300 to 600 mg
of epirubicin/m2, with the latter being equiactive to 200 or 400 mg of doxorubicin/m2, respectively.
Patients will therefore be exposed to cumulative doses of 200 to 400 mg of doxorubicin
equivalents/m2, which is equal to or lower than the cumulative dose associated with a 5% risk of
systolic dysfunction in patients without risk factors. This should help to identify patients who
developed early diastolic dysfunction with preserved LVEF. Recruitment is competitive by center
and tumor type. Eleven italian centers participate in INTERACT .
Seven ± three days after completing chemotherapy, patients with echocardiographic
indices of diastolic dysfunction, and/or persistent elevations of TnI or Nt-proBNP, are randomized
1:1 to receive ranolazine or most common therapy (i.e., drugs or combination of drugs, like β
blockers or others, that the cardiologist feels appropriate according to his/her own experience at
his/her own institution). This is the interventional arm of INTERACT. In the light of a preliminary
experience at the Coordinating Center, it is expected that ~40% of the recruited patients should
enter the interventional arm. Patients randomized to ranolazine or most common therapy are
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reassessed at five weeks and then enter a monthly follow-up that ends at six months with a final
assessment by both echocardiography and TnI and Nt-proBNP measurements. Patients who show
“normal” at an early post-chemotherapy assessment enter an institutional follow-up whose
modalities are left to the investigators’ discretion. The institutional follow-up ends at six months with
a complete reassessment by both echocardiography and TnI and Nt-proBNP measurements
(FIGURE 3).
The objectives of INTERACT
The interventional arm of INTERACT is designed to meet the following objectives: efficacy
with which five weeks ranolazine relieves echocardiographic and/or biohumoral indices of
chemotherapy-induced diastolic dysfunction (primary efficacy endpoint), tolerability of five weeks
ranolazine in post-chemotherapy cancer patients (primary safety end point), tolerability of six
months ranolazine (secondary safety endpoint ), tolerability of five weeks to six months ranolazine
in comparison with most common therapy (exploratory safety endpoint).
The observational arm of INTERACT aims at approximating the incidence of
echocardiographic and/or biohumoral indices of diastolic dysfunction in patients who had proven
“normal” at an earlier post-chemotherapy assessment. The objectives of this arm are to retrieve
information that could prove useful in forthcoming clinical studies. Should a significant incidence of
diastolic dysfunction occur in the observational arm, one might consider starting ranolazine in any
patient who completed antitumor chemotherapies.
Post hoc research considerations
Patients' accrual started in December 2010. At the time when this Perspective was
submitted, 84 patients had been successfully screened and maintained in the study, which
corresponds to a net accrual rate of approximately 5 patients/month in the face of the participation
of 11 clinical centers. Although study progression was slowed down by unavoidable delays in the
involving of participating centers and by patients’ drop out due to tumor-related clinical events,
these low figures confirm that INTERACT had to go through the bottleneck of very rigorous
inclusion/exclusion criteria. With that said, the bottleneck was worth of all such effort. After
INTERACT had been designed or the first patient had been recruited in it, several research papers
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appeared and denoted possible confounding factors in the interpretation of ranolazine effects. In
pressure overloaded rats, INa,Late increases correlated with the expression of neuronal isoforms
Nav1.1 and Nav1.6 rather than of Nav1.5 (Xi et al., 2009). In oxidative stress-prone
deoxycorticosterone acetate-salt hypertensive mice, which in principle should express a
hyperactive INa,Late, ranolazine relieved diastolic dysfunction by modulating Ca2+ effects on the
contractile apparatus rather than by inhibiting INa,Late (Lovelock et al., 2012). In established models
of mechanosensitivity, ranolazine bound to Nav1.5 by utilizing sites other than the canonical F1760
(Beyder et al., 2012). Each of these reports alludes to alternative modes of action of ranolazine in
patients with comorbidities. Probing ranolazine in cancer patients without comorbidities may
therefore be rewarding to the extent it allows for detecting and treating diastolic dysfunction under
the cleanest possible conditions, i.e., when diastolic dysfunction built on chemotherapy activation
of INa,Late and ranolazine relieved diastolic dysfunction by binding to its known sites in Nav1.5. Once
ranolazine efficacy was defined in such settings, clinical studies of more complex patients would be
easier to design and to interpret. The experience gained through INTERACT may also help to
design studies of the effects of ranolazine on other echocardiographic indices of subclinical
cardiotoxicity, like e.g., decreases of myocardial strain (Sawaya et al. 2012). Normal ranges of
global or segmental strain, and applicability of reference values to different operational procedures,
were defined when INTERACT had already been designed (Dalen et al., 2010; Marwick et al.,
2009).
Previous studies suggested that ranolazine could be used to treat diastolic dysfunction.
Ranolazine improved diastolic function in patients with previous transmural MI (Hayashida et al.,
1994), or in patients with long QT syndrome 3 due to SCN5A gene mutations and slow inactivation
of INa,Late (Moss et al., 2008); however, these were limited studies of the effects of acute
intravenous ranolazine. At the dosages approved in US (500 mg bid for a week and 1000 mg bid in
maintenance therapy), oral ranolazine improved echocardiographic indices of myocardial
performance in patients with stable angina. This latter study did not focus primarily on diastolic
dysfunction and did not assess ranolazine effects at pre-specified checkpoints that could tell how
quickly and effectively oral ranolazine exerted and maintained its effects; in fact, patients were
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assessed anytime from 30 to over than 200 days after ranolazine was commenced (Figueredo et
al., 2011). INTERACT is entirely focussed on diastolic dysfunction, titrates oral ranolazine through
the dosages approved in EU (375 mg bid for two weeks, followed by 500 mg bid for 10 days and
750 mg bid until the end of the study), and sets its primary and secondary endpoints at
prespecified times that should tell more about how quickly and persistently ranolazine exerted its
effects.
Conclusions and perspectives
Neither oncology nor cardiology would embrace the rationale of INTERACT. In everyday
clinical practice both oncologists and cardiologists tend to underestimate the importance of early
diastolic dysfunction as a culprit of the lifetime risk of HF or ischemic disease. Cardiovascular
assessment of cancer patients remains almost invariably bound to measuring LVEF. INTERACT is
a good example of how pharmacology can work for cardio-oncology in improving cardiac
surveillance and management of patients exposed to cardiotoxic chemotherapeutics. INTERACT
combines appreciation of the mode of action of ranolazine with the need for intercepting and
treating early diastolic dysfunction before it slowly progressed toward late sequelae.
Results from INTERACT will pave the road to further studies of ranolazine in cancer
patients, which is a steadily growing population at risk for cardiotoxicity. INTERACT should also
help to define the working philosophy of cardio-oncology teams and to dignify the role of
pharmacologists in such teams.
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AUTHORSHIP CONTRIBUTION
G.M. designed INTERACT, served as Study Coordinator, and wrote this Perspective
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FOOTNOTES
INTERACT is promoted by Menarini Group. G.M. acknowledges financial support from University
Campus Bio-Medico (Special Project Cardio-Oncology) and TCI-Telecomunicazioni Italia
(unrestricted charity fund).
Reprints request to:
Giorgio Minotti, MD
CIR and Drug Sciences
University Campus Bio-Medico
Via Alvaro del Portillo 21
00128 Rome-ITALY
Phone: 011-39-06-225419109
FAX 011-39-06-22541456
1Belardinelli L. (2010) personal communication
2Radiotherapy for left-sided breast cancer has become much safer than it was in the past;
therefore, women scheduled to receive post-chemotherapy radiation to the left chest wall or breast
are not considered at risk for multiple hits and can be recruited into INTERACT.
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LEGENDS FOR FIGURES
Figure 1 Ranolazine-inhibitable INa,Late and its role in diastolic dysfunction and ischemia
In the ischemic myocardium, delayed and/or incomplete inactivation of INa,Late causes elevated
intracellular Na+ that exchanges with extracellular Ca2+ via the reverse mode Na+-Ca2+ exchanger.
Excess Ca2+ entry causes diastolic wall tension, and the latter causes ischemia that perpetuates
INa,Late activation. By inhibiting INa,Late, ranolazine interrupts the vicious cycle between ischemia and
diastolic dysfunction.
NaCh, Na+ channel; NCX, Na+-Ca2+ exchanger.
Figure 2 Chemotherapy-induced diastolic dysfunction and the role of ranolazine-inhibitable INa,Late
Panel A: Anthracyclines induce multiple mechanisms of diastolic dysfunction, possibly mediated or
amplified by ranolazine-inhibitable INa,Late. ROS, reactive oxygen species; RNS, reactive nitrogen
species.
Panel B: Ranolazine inhibition of INa,Late mitigates diastolic dysfunction induced by vicious cycles
between anthracyclines and nonanthracycline chemotherapeutics.
Figure 3 Essential flowchart of the INTERACT study
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Na+
Ca2+
Ca2+
Na+Na+
Ranolazine
Ca2+
Ca2+ overload
Wall tension
Ischemia
NaCh NCX
Figure 1
Ischemia
1 Ca2+
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ROS and RNS formation
Increased oxygenconsumption
Cytoplasmic Ca2+
overload
Diastolic dysfunctionNa
Ranolazine
INa,Lateaactivation
Metabolic ischemia
Anthracyclines
A
B
Endothelial dysfunction
Nonanthracyclinechemotherapeutics
Anthracyclines
Diastolicdysfunction
INa,Late activation
Ischemia
Figure 2
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One week post-chemotherapy assessment
Diastolic dysfunction at echocardiography and/or
Nt-proBNP and/or TnI elevations
No abnormality
Ranolazine Most common therapy
Screening
Chemotherapy
5 weeks reassessment by echocardiography, Nt-proBNP, TnI
Monthly follow-up
6 months reassessment (secondary endpoint)
Institutional follow-up
6 months reassessment (exploratory endpoint)
Exclude pre-existingdiastolic dysfunction,
LVEF <50%, cardiovascular and/or metabolic comorbidity, altered TnI and/or Nt-
proBNP, post-chemotherapy targetedtherapy or mediastinal
irradiation
Figure 3
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