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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

JPET Fast Forward. Published on July 1, 2013 as DOI:10.1124/jpet.113.204057

Copyright 2013 by the American Society for Pharmacology and Experimental Therapeutics.

This article has not been copyedited and formatted. The final version may differ from this version.JPET Fast Forward. Published on July 1, 2013 as DOI: 10.1124/jpet.113.204057

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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

[email protected]

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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