Ranolazine: NewParadigm forManagementof Myocardial Ischemia,Myocardial Dysfunction,and Arrhythmias

Peter H. Stone, MD

KEYWORDS� Myocardial ischemia � Angina � Ranolazine � Heart failure� Diastolic dysfunction

.com

Anti-ischemia medications have traditionallyfocused on optimizing the determinants of themyocardial O2 supply: demand balance. Becausemyocardial oxygen extraction is maximal at rest,the only way to improve the balance pharmacolog-ically has been to reduce myocardial O2 demand(ie, heart rate, blood pressure or afterload,myocardial contractility, or preload). The approvedantianginal medications in the United States areeffective by reducing one or more of these O2

demand determinants (Table 1).There are many patients, however, who have

chronic coronary disease in whom this pharmaco-logic approach is inadequate. Many patients eithercannot tolerate these conventional agents or havecontinuing symptoms of ischemia and anginadespite their use.1 Ranolazine, which was ap-proved by the US Food and Drug Administrationin January 2006, provides a mechanism of actionto treat ischemia that has not hitherto been avail-able. Ranolazine is effective to reduce manifesta-tions of ischemia and angina, and it also holdspotential promise to be effective in the manage-ment of left ventricular dysfunction, particularly di-astolic dysfunction, and arrhythmias. This articleprovides an update on the available studies con-cerning the value of ranolazine across the spec-trum of cardiovascular disease.

Cardiovascular Division, Brigham and Women’s Hospital, H02115-6110, USAE-mail address: pstone@partners.org

Cardiol Clin 26 (2008) 603–614doi:10.1016/j.ccl.2008.06.0020733-8651/08/$ – see front matter ª 2008 Elsevier Inc. All

MECHANISM OFACTION

Ranolazine was first believed to be effective byinhibiting free fatty acid metabolism,2 but it waslater appreciated that ranolazine exerted thiseffect only at serum levels that are much higherthan those observed in therapeutic usage.3 Themechanism of action now seems to be relatedto inhibition of the late inward sodium channel(late INa),4 which pathologically remains open ina wide variety of adverse stimuli to the myocar-dium. Electrical activation of the cardiomyocytesleads to brief opening of the membrane sodiumchannel, through which sodium ions rapidly enterthe cell, generating the rapid depolarization orupstroke of the action potential (Fig. 1A).4 In thenormal setting, the inward sodium channels theninactivate rapidly and remain closed during theplateau phase of the action potential. Other ionchannels open following electrical activation,including calcium channels, and the calcium ionsthat enter the cell during the plateau phase of theaction potential then trigger the release of the largestores of calcium ions from the sarcoplasmic retic-ulum. This increased concentration of cytoplasmiccalcium initiates the interaction between actin andmyosin and enables the contraction process tooccur (see Fig. 1A). Following the myocardial

arvard Medical School, 75 Francis Street, Boston, MA

rights reserved. card

iolo

gy.th

ecli

nics

Table1Antianginal pharmacologic management

Determinant of O2Demand b-Blocker Nitrates

CaDD Blocker CaDD Blocker

Dihydropyridine Verap/Dilt

Heart rate YY 0 [/[[ YY

Afterload (BP) Y Y YYYY YY

Preload 0 YYY 0 0

Contractility YY [ [[ YY

Determinant of O2 supply

Vasomotor tone [ YY YYYY YYYY

Abbreviations: BP, blood pressure; verap/dilt, verapamil/diltiazem; 0, no effect.

Stone604

contraction, calcium ions are actively taken upback into the sarcoplasmic reticulum again andmyocardial relaxation occurs.

In the setting of a wide variety of myocardialinsults, however, including myocardial ischemia,hypertrophy, and oxidative stress, the late sodiumchannels either fail to inactivate (ie, fail to close) orreopen, such that sodium ions continue to enterthe cell (see Fig. 1B).4,5 This intracellular overloadof sodium ions leads to several major contractility,metabolic, and electrophysiologic disturbances.6

The elevation of intracellular sodium concentrationleads to an increased exchange of intracellularsodium for extracellular calcium through theNa1/Ca11 exchanger mechanism, such that theinitial sodium overload leads to a subsequentintracellular calcium overload. The increased cyto-solic calcium from the calcium overload stateleads to the continued exposure of the actin andmyosin contractile elements to the calcium ions,leading to a tonic contracture (see Fig. 1B). Inthe intact heart, this increased diastolic stiffness

Normal

Sodium

Current

Action

Potential

Twitch

0

Late

Peak

Phasic

Delayed and/or Inco

Inactivation

(Ischemia, Failure,

0

Late

Peak

Phasic

A B

leads to an abnormal elevation in myocardialcontractile work, oxygen consumption, and com-pression of the vascular space during diastole.4,7

Compression of the vascular space causesa reduction in myocardial blood flow, which furtherreduces myocardial O2 supply. This deleteriouspositive feedback system is detrimental in thatthe presence of ischemia leads to further exacer-bation of ischemia (Fig. 2).

Ranolazine reduces the late sodium influx ina concentration-, voltage-, and frequency-dependent manner.4,6,7 By preventing the mostupstream deleterious consequence of myocardialcellular dysfunction (ie, the intracellular sodiumoverload), all of the downstream consequencesof the sodium overload, and the subsequentcalcium overload, are reduced or prevented. Inanimal models ranolazine thus facilitates diastolicrelaxation, preserves myocardial blood flow duringischemia and reperfusion, reduces myocardial O2

consumption, and restores electrical stability.4,6–8

In healthy nonischemic, nonfailing myocytes, in

mplete

LVH)

Tonic

Fig.1. Relation between late Na1 currentand ventricular action potential andcontraction. (A) Normal conditions.(B) Delayed or incomplete inactivationin the setting of ischemia, heart failure,or left ventricular hypertrophy (FromBelardinelli L, Antzelevitch C, Fraser H.Inhibition of late (sustained/persistent)sodium current: a potential drug targetto reduce intracellular sodium-dependent calcium overload and itsdetrimental effects on cardiomyocytefunction. Eur Heart J 2004;6:14; withpermission.)

Ischemia

Late INa

Na+

Overload

Diastolic relaxation failure

(Increased diastolic tension)

Extravascular compression

Ca++

Overload

Ranolazine:Inhibits the late inward

Na current

Fig. 2. Mechanism of action of ranolazine.

Ranolazine: New Paradigm for Management 605

which the contribution of late INa is small, the drugdoes not have a measurable effect on cardiovas-cular performance at therapeutic plasma concen-trations.9 The effect of ranolazine on late INa ismore pronounced in ischemic or failing myocytesin which the current is amplified.9 Each of thesepharmacologic effects may have important thera-peutic application for patients who havecardiovascular disease, as discussed later.

PHARMACOKINETICS ANDMETABOLISM

Ranolazine is an active piperazine derivative avail-able in oral and intravenous forms and is nowmanufactured in a sustained-release form.9 Itsmaximal plasma concentration is typically 4 to6 hours after administration, and the average ter-minal elimination half-life is approximately 7 hours.The peak/trough difference is 1.6-fold with dosingof 500 to100 mg twice a day.9 Ranolazine plasmaconcentrations that are therapeutically effectivefor chronic angina are in the range of 2 to6 mmol/L.9 Oral bioavailability is in the range of30% to 55%. Most of the metabolic biotransfor-mation is through the cytochrome P450 3A4-mediated pathway,9 which is critical because

Ranolazine

Consequences of Isc

• Electrical instab• Myocardial dys

( systolic functdiastolic stiffn

Conventionalanti-ischemicmedications

ß blockersNitratesCa++ blockers

Compressi

of nutritiv

blood vess

Ischemia

(Ca++

overload)

O2

Demand

• Heart rate• Blood pressure• Preload• Contractility

O2

Supply

Development of Ischemia

compounds such as ketoconazole, which inhibitthe CYP3A isoenzymes, increase ranolazine levelsin the range of 2.5 to 4.5 fold.9 Clearance of rano-lazine is reduced by renal insufficiency and moder-ate hepatic impairment.9

Drug–drug interactions primarily are related toeffects on the CYP3A metabolic pathway.9 Diltia-zem, ketoconazole, verapamil, macrolide antibi-otics, HIV protease inhibits, and grapefruit juiceinhibit the CYP3A enzyme system, and theirconcomitant use with ranolazine should be donewith caution. Ranolazine also is a substrate andan inhibitor of P-glycoprotein. Verapamil, which in-hibits P-glycoprotein, increases the absorption ofranolazine, with a consequent increased in plasmalevels. Ranolazine increases digoxin levels.

THERAPEUTIC USESChronic Angina Pectoris

Conventional anti-ischemia medications reducethe development of ischemia primarily by reducingthe determinants of myocardial O2 demand: heartrate, blood pressure, preload, or contractility(Fig. 3). As myocardial ischemia develops intracel-lular calcium overload occurs, which leads to theconsequences of ischemia, including systolic anddiastolic myocardial dysfunction and electricalinstability. Ranolazine has no clinically meaningfuleffects on the myocardial O2 demand determi-nants, but exerts its anti-ischemic effect bypreventing the calcium overload state and therebyreducing the subsequent myocardial stiffness thatleads to reduced myocardial perfusion (see Fig. 3).A recent study demonstrated that the dose-relatedimprovement in myocardial ischemia at submaxi-mal and maximal exercise in patients who hadstable coronary artery disease was attributable toan improvement in myocardial blood flow withoutmeaningfully affecting heart rate or blood pres-sure.10 One can therefore anticipate that ranola-zine would be an ideal complementary agent to

hemia

ilityfunctionion/ess)

on

e

els

Fig. 3. Sites of action of anti-ischemiamedication.

Stone606

be used with medications that reduce the develop-ment of ischemia by reducing O2 demand.

MonotherapyThe early studies of ranolazine in patients who hadstable angina used the immediate-release formu-lation, whereas the more recent studies haveused the sustained-release formulation. In com-parison with placebo, ranolazine in the immedi-ate-release formulation significantly reducedanginal episodes and nitroglycerin use, and signif-icantly improved exercise duration and time toexercise-induced myocardial ischemia,11 andwas at least equally as effective as atenolol100 mg every day (Fig. 4). The anti-ischemia effectof atenolol was attributable to its well-knownreduction in the rate–pressure product at restand during exercise, whereas the anti-ischemiceffect of ranolazine occurred without any appre-ciable change in the determinants of myocardialO2 demand (Fig. 5).11

The Monotherapy Assessment of Ranolazine inStable Angina (MARISA) trial investigated theeffect of the sustained-release formulation as sin-gle agent therapy of 500 mg twice a day, 1000 mgtwice a day, or 1500 mg twice a day versus pla-cebo twice a day in 191 patients who had chronicexertional angina with reproducible treadmill-induced myocardial ischemia and angina in a4-week, double-blind, placebo-controlled cross-over trial.12 All three doses resulted in a significant,dose-dependent increase in exercise duration,exercise time to angina, and exercise time to1-mm ST segment depression at trough and atpeak drug effect compared with placebo

Fig. 4. Therapeutic effects of placebo (n 5 142), ranolazineand ischemic ST-segment depression in patients who have sCocco G, et al. Comparative efficacy of ranolazine versu2005;95:313; with permission.)

(P < .005), although the incremental benefit was at-tenuated at dosages greater than 1000 mg twicea day.12 The maximal increase in exercise durationcompared with placebo was 56 seconds, whereasthe maximal increase in time to angina or time to1-mm ST-segment depression was 69 seconds(Fig. 6).

Combination regimensThe Combination Assessment of Ranolazine inStable Angina (CARISA) trial was designed to eval-uate the effect of the addition of ranolazine toa regimen of concomitant antianginal drugs,including atenolol (50 mg every day), diltiazem(180 mg every day), or amlodipine (5 mg everyday).13 A total of 823 patients were studied in a par-allel design, and ranolazine 750 mg or 1000 mg orplacebo twice a day was administered in additionto the concomitant medications. Exercise testswere performed 2, 6, and 12 weeks after random-ization. The addition of ranolazine was associatedwith a significant reduction in anginal frequencyand nitroglycerin consumption, and an increasein exercise duration, time to angina, and time to1-mm ST-segment depression compared withplacebo both at trough and peak drug effect(Fig. 7). There was not a major difference betweenthe ranolazine 750 mg and 1000 mg twice a dayregimens. The increase in exercise duration of115.6 seconds above baseline in both ranolazinegroups versus 91.7 seconds in the placebo group(P 5 .01) did not depend on changes in bloodpressure or heart rate, and this improvement inperformance was sustained over the 12 weeks oftherapy. The treatment-by-background interaction

(n 5 142), and atenolol (n 5 142) on exercise tolerancetable coronary disease. (From Rousseau MF, Pouleur H,s atenolol for chronic angina pectoris. Am J Cardiol

10,000

20,000

30,000

40,000

Rat

e-Pr

essu

re P

rodu

ct(m

mH

g·m

in-1

± SE

)

Minutes on treadmill

Placebo

Ranolazine

Atenolol

0 3 6 9 12 15 18

n = 96 71 75 49 28 4 1n = 97 73 76 66 31 8 1n = 97 73 75 57 24 1 0

* * * * * Atenolol

Placebo

Ranolazine* p <0.001 vs placeboFig. 5. Anti-ischemic effect of ranolazinewithout affecting heart rate or bloodpressure at rest or during exercise.(From Rousseau MF, Pouleur H, Cocco G,et al. Comparative efficacy of ranolazineversus atenolol for chronic anginapectoris. Am J Cardiol 2005;95:314; withpermission.)

Ranolazine: New Paradigm for Management 607

term indicated no evidence of differential treat-ment effect according to background therapy re-ceived. Adverse events were reported in 26.4%of patients in the placebo group, 31.2% of patientsin the ranolazine 750 mg group, and 32.7% of theranolazine 1000 mg group. The most commondose-related adverse effects were constipation,dizziness, nausea, and asthenia, which occurredin less than 7% of the ranolazine-treated patientsand less than 1% of the placebo-treated patients.There was a small, dose-related increase in theQTc interval of 6.1 and 9.2 milliseconds in the750 mg and 1000 mg ranolazine groups, respec-tively, but there were no evident arrhythmias.Five patients taking 1000 mg ranolazine twicea day experienced syncope, but all were also tak-ing an angiotensin-converting enzyme inhibitorand 4 of the 5 were also taking diltiazem, whichis known to increase ranolazine levels. Althoughlittle or no effect of ranolazine was observed onblood pressure on 750 or 1000 mg twice a daydosages, postural hypotension and syncopehave occurred in healthy volunteers given higherdoses, up to 2000 mg twice a day, and this isbelieved likely because of a1-adrenergic receptorblocking activities at higher plasma concentra-tions.13 The patients in CARISA treated with

ranolazine who were diabetic experienced a signif-icant reduction in hemoglobin AIc compared withplacebo (�0.70%, P 5 .002), although the mecha-nism of this improvement is not clear.

A more recent study investigated the antianginaleffect of ranolazine versus placebo given to 565 pa-tients who had persisting angina symptoms de-spite maximal dose amlodipine (10 mg every day)(Efficacy of Ranolazine in Chronic Angina [ERICA]trial).14 Compared with placebo, the addition of ra-nolazine 1000 mg twice a day was associated witha significant reduction in weekly anginal episodesand nitroglycerin consumption (to 3.31 episodes/wk on placebo versus to 2.88 episodes/wk on ra-nolazine, P 5 .028).14 There was a consistent treat-ment effect of ranolazine across the subgroupsanalyzed, including those also on long-acting ni-trates versus those not on long-acting nitrates,men versus women, and patients aged less than65 years versus those older than 65 years. An inter-esting subgroup analysis dividing patients on thebasis of being above or below the median ofweekly anginal frequency (4.5 episodes) indicatedthat those patients who had more frequent anginaper week had a much more marked beneficial re-sponse to the addition of ranolazine, comparedwith those patients who had less frequent angina,

Fig. 6. Monotherapy with ranola-zine increases exercise performanceat trough and peak pharmacologiceffect: the MARISA trial. (FromChaitman BR, Skettino SL, ParkerJO, et al. Anti-ischemic effects andlong-term survival during ranola-zine monotherapy in patientswith chronic severe angina. Modi-fied from J Am Coll Cardiol2004;43:1378; with permission.)

Fig. 7. Effect of ranolazine 1000 mg twice a day on exercise treadmill performance when combined with atenolol50 mg every day, diltiazem 120 mg every day, or amlodipine 5 mg every day. (From Chaitman BR, Pepine CJ, ParkerJO, et al. Effects of ranolazine with atenolol, amlodipine, or diltiazem on exercise tolerance and angina frequency inpatients with severe chronic angina: a randomized controlled trial. Data from JAMA 2004;291:312.)

Stone608

in reduction in angina, nitroglycerin consumption,and Seattle Angina Questionnaire (Fig. 8).14 Theseresults suggest that those patients who have themost frequent angina may have the most sustainedleft ventricular dysfunction from their repetitivebouts of ischemia, and that these patients are theones most likely to experience a substantial benefitfrom ranolazine’s effects on ischemia-associatedleft ventricular dysfunction.

0

1

2

3

4

5

6

Placebo + Amlodipine

Angina

Frequency

NTG

Use

Angina

Frequency

NTG

Use

P<0.001P=0.029

P=0.036

P=0.28

≤ 4.5 AnginaEpisodes/Wk

> 4.5 AnginaEpisodes/Wk

Num

ber/W

k

Fig. 8. Effect of ranolazine 1000 mg twice a day in patientdipine therapy: the ERICA trial. (From Stone PH, Gratsianskzine when added to treatment with amlodipine: the ERICAColl Cardiol 2006;48:572; with permission.)

Unstable Angina/Non–ST Segment ElevationMyocardial Infarction

The recent MERLIN TIMI-36 trial addressed thevalue of an intravenous infusion of ranolazine, fol-lowed by oral ranolazine, in patients who hada non–ST segment elevation acute coronary syn-drome (ACS).15 A total of 6560 patients who hadeither unstable angina or NSTEMI were enrolledwithin 48 hours of ischemic symptoms and were

0

10

20

30

Ranolazine + Amlodipine

Angina Frequency Domain(Seattle Angina Questionnaire)

P<0.001P=0.57

≤ 4.5 AnginaEpisodes/Wk

> 4.5 AnginaEpisodes/Wk

Cha

nge

from

Bas

elin

ein

SAQ

Sco

re

s who have refractory angina despite maximum amlo-y NA, Blokhin A, et al. Antianginal efficacy of ranola-(Efficacy of Ranolazine in Chronic Angina) trial. J Am

Ranolazine: New Paradigm for Management 609

treated with ranolazine (initiated intravenously andfollowed by oral ranolazine extended release 1000mg twice a day) or matching placebo. They werefollowed up for a median of 348 days. The primaryefficacy endpoint was a composite of cardiovas-cular death, myocardial infarction (MI), or recurrentischemia and occurred in 21.8% of the ranolazine-treated patients and 23.5% of the placebo-treatedpatients (hazard ratio [HR] 0.92, 95% CI 0.83–1.02,P 5 .11) (Fig. 9A). Although there was no differ-ence in the occurrence of the primary compositeendpoint between the two treatment groups, orin two of the individual components of the primarycomposite endpoint (cardiovascular death or MI),there was a significant difference in the endpointof recurrent ischemia (13.9% in the ranolazine-treated patients versus 16.1% in the placebo-treated group; HR 0.87, 95% CI 0.76–0.99, P 5.03) (see Fig. 9B and Fig. 10). A trend toward anearly reduction in recurrent ischemic complica-tions with ranolazine was evident with respect tothe 30-day endpoint of cardiovascular death, MI,severe recurrent ischemia, or positive Holter for is-chemia (P 5 .055). An effect of long-term treat-ment with ranolazine on angina was evident withrespect to several prespecified exploratory end-points: reduction in worsening angina by at leastone Canadian Cardiovascular Society class re-quiring intensification of medical therapy, less fre-quent escalation in antianginal medication, andimprovement in anginal frequency using the Seat-tle Angina Questionnaire. There was no significantheterogeneity of the effect of ranolazine on the pri-mary endpoint across the major subgroupsexamined.

Ranolazine also had a significant effect of pre-venting ventricular and atrial arrhythmias in thesehigh-risk patients who had a non–ST elevationACS,16 as discussed later.

In a substudy analysis stratifying patients on thebasis of brain natriuretic peptide (BNP) measure-ments obtained at the time of randomization,

Composite 1°Endpoint(Death, MI, Recurrent Ischemia)

HR 0.92 (p=0.11)

Components of 1°Endp

CV Death/MI Recurrent

21.8 23.5

5

10

15

20

25

10.4

5

10

15

20

13.10.4

HR 0.99 (p=0.87) HR 0.87

Ranolazine Placebo Ranolazine Placebo Ranolaz

A B

5

10

15

20

those patients who had an elevated BNP greaterthan 80 pg/mL, likely reflecting diastolic stiffnessresulting from more severe or more prolongedischemia, experienced a significantly higherincidence of cardiovascular death, MI, or recurrentischemia compared with patients who had ACSwith a BNP value less than 80 pg/mL(P < .001).17 Furthermore, ranolazine was associ-ated with a significant reduction in the compositeprimary endpoint of cardiovascular death, MI, orrecurrent ischemia in those high-risk patientswho had an elevated BNP (P 5 .009), whereasthere was no beneficial effect in low-risk patientswho had a normal BNP value.17

The safety of ranolazine was confirmed in thislarge clinical trial. There was no difference in mor-tality between patients treated with ranolazineversus placebo, nor sudden death. The incidenceof symptomatic documented arrhythmias through-out the duration of the study was also similar in thetwo treatment groups (P 5 .84). Discontinuation oftreatment because of an adverse event occurredin 28% in the ranolazine group to 22% in theplacebo group (P < .001). Discontinuation becauseof an adverse event was reported significantlymore frequently among patients receiving ranola-zine compared with patients receiving placebo(8.8% versus 4.7%, P < .001). The most frequentadverse events, occurring in more than 4%of patients, were dizziness (13% versus 7%), nau-sea (9% versus 6%), and constipation (9% versus3%). Syncope occurred in 3.3% of the patientsreceiving ranolazine and 2.3% of the patientsreceiving placebo (P 5 .01). Most of these werebelieved to be vasovagal syncope. Only two casesof torsades de pointes were noted in the study,one in each treatment group.

Electrophysiologic Effects of Ranolazine andEfficacy as an Antiarrhythmic Agent

Ranolazine exerts several effects on cardiac ioncurrents at concentrations within the therapeutic

oint

Ischemia

916.1

(p=0.03)

ine Placebo

Fig. 9. Effect of ranolazine in patientswho have a non–ST elevation ACS: theMERLIN trial. (From Morrow DA, SciricaBM, Karwatowska-Prokopczuk E, et al.Effects of ranolazine on recurrent cardio-vascular events in patients with non–STelevation ACS: the MERLIN-TIMI 36 ran-domized trial. Data from JAMA2007;297:1779.)

Fig.10. Kaplain-Meier estimated rates of cardiovascular death or MI and recurrent ischemia. (From Morrow DA,Scirica BM, Karwatowska-Prokopczuk E, et al. Effects of ranolazine on recurrent cardiovascular events in patientswith non–ST elevation ACS: the MERLIN-TIMI 36 randomized trial. JAMA 2007;297:17780; with permission.)

Stone610

range of 2 to 6 mmol/L, which include inhibition of IKr,late INa, and late ICa,L (Fig. 11).6 Although inhibitionof IKr by ranolazine prolongs the action potential du-ration, inhibition of the late INa and the late ICa

shorten the action potential duration such that thenet effect on the action potential duration, or QTc,is usually modest (ie, in the range of 5–10 millisec-onds). In experimental animals and tissue prepara-tions ranolazine actually shortens or normalizesthe action potential duration that is prolongedfrom ischemia or exposure to arrhythmogeniccompounds, such as d-sotalol (Fig. 12A, B).6

It is now well appreciated that development ofdrug-induced torsades de pointes requires notonly prolongation of the action potential and theQTc interval, but also the presence of early after-depolarizations and increased dispersion of repo-larization across the myocardium. Althoughranolazine exerts a minimal effect of prolonging

Fig. 11. Effect of ranolazine on electrophysiologic ioncurrents across the myocyte cell membrane. (FromAntzelevitch C, Belardinelli L, Zygmunt AC, et al.Electrophysiological effects of ranolazine, a novelantianginal agent with antiarrhythmic properties.Circulation 2004;110:906; with permission.)

the QT interval, it exerts several other protectiveeffects: (i) ranolazine reduces the incidence ofearly afterdepolarizations (see Fig. 12A), and (ii)ranolazine does not exacerbate the transmuraldispersion of repolarization, which is associatedwith ischemia and exposure to arrhythmogenicdrugs.6 In the experimental animal ranolazinedoes not cause torsades de pointes,6 and, asnoted earlier in the experience in the MERLIN trial,there was only one case of torsades in the patientswho had a non–ST elevation ACS, and this was thesame incidence as in the placebo group.16

Although ranolazine has not been studied asa primary antiarrhythmic agent, it has been effica-cious as an antiarrhythmic agent in the large-scalestudies that have included continuous ECG moni-toring.16 In the MERLIN trial 97% of the6560 patients who had ACS had a continuousECG that was interpretable for analysis. Treatmentwith ranolazine was associated with a significantreduction in ventricular arrhythmias, including ven-tricular tachycardia greater than or equal to 3, 4, or8 beats at a rate of 100 beats per minute (bpm) orgreater (P < .001), but had no effect on sustainedventricular tachycardia greater than 30 seconds(Table 2 and Fig. 13). Ranolazine also reducedthe incidence of supraventricular arrhythmias120 bpm or greater lasting 4 beats or more(P < .001), and was associated with a trend towardreducing the incidence of new-onset atrial fibrilla-tion (P 5 .08) (see Table 2). Among several high-risk subgroups, including patients who had priorheart failure, reduced left ventricular function, pro-longed QTc interval at baseline, and high TIMI RiskScore (5–7), ranolazine consistently reduced theincidence of ventricular tachycardias lasting8 beats or more, although there was no differencein sudden cardiac death.16 Ranolazine alsoreduced the incidence of bradycardia less than

Fig. 12. Effect of ranolazine to normalize the actionpotential duration and suppress early afterdepolariza-tions in M cells (A) and Purkinje fiber preparations(B). (From Antzelevitch C, Belardinelli L, ZygmuntAC, et al. Electrophysiological effects of ranolazine,a novel antianginal agent with antiarrhythmic proper-ties. Circulation 2004;110:909; with permission.)

Ranolazine: New Paradigm for Management 611

45 bpm for at least 4 beats. It is not clear whetherthe antiarrhythmic effects observed withranolazine were attributable to prevention of ische-mia-associated arrhythmias by preventing theischemia itself, or from a more primary antiarrhyth-mic effect related to its effect on membrane ionchannels.

Table 2Effect of ranolazine on tachyarrhythmias detected after n

Ranolazine n (%)

Ventricular arrhythmias

VT R 3 beats R 100 bpm 1646 (52.1)

VT R 4 beats R 100 bpm 662 (20.9)

VT R 8 beats (lasting <30 s) 166 (5.3)

Polymorphic VT R 8 beats 38 (1.2)

Sustained VT (R30 s) 14 (0.44)

Monomorphic 4 (0.13)

Polymorphic 10 (0.32)

Supraventricular arrhythmias

New-onset atrial fibrillation 55 (1.7)

Other SVT R 120 bpm lastingat least 4 beats

1413 (44.7)

Abbreviations: bpm, beats per minute; SVT, supraventricular t

New studies are being considered to investigatethe more primary use of ranolazine as an antiar-rhythmic agent for atrial or ventricular arrhythmias.

Future Applications

Diastolic heart failureEvidence in experimental animals suggests thatranolazine may provide a unique role in the man-agement of patients who have heart failure, partic-ularly diastolic heart failure associated withischemic cardiomyopathy and left ventricularhypertrophy. Abnormal late INa, and subsequentsodium ion and calcium ion overload, is a commoncharacteristic of myocardial dysfunction associ-ated with myocardial ischemia, left ventricularhypertrophy, and various conditions associatedwith oxidative stress.4 Ranolazine is uniquelyable to treat the abnormal late INa, and it canthereby prevent the sodium overload and the con-sequent calcium overload and the abnormal leftventricular diastolic function that ensues. For ex-ample, in isometrically contracting ventricularmuscle strips from end-stage failing human hearts,ranolazine (10 mmol/L) significantly reduced thefrequency-dependent increase in diastolic dys-function by approximately 30% without signifi-cantly affecting sarcoplasmic reticulum Ca11

loading.18 To investigate the mechanism of thisobserved amelioration of diastolic dysfunction inthe human heart, isolated ventricular rabbit myo-cytes were exposed to ATX-II, a toxin that mimicsthe effects of abnormal opening of the late INa, andranolazine prevented the increases in late INa andintracellular sodium and diastolic calcium ionscaused by ATX-II.18 In isolated ejecting/working

on^ST segment elevationmyocardial infarction

Placebo n (%) RR (95% CI) P value

1933 (60.6) 0.86 (0.82–0.90) <0.001

941 (29.5) 0.71 (0.6–0.78) <0.001

265 (8.3) 0.63 (0.52–0.76) <0.001

46 (1.4) 0.83 (0.54–1.28) 0.40

14 (0.44) 1.01 (0.48–2.13) 0.98

7 (0.22) 0.59 (0.17–2.06) 0.37

7 (0.22) 1.41 (0.52–3.78) 0.46

75 (2.4) 0.74 (0.52–1.05) 0.08

1752 (55.0) 0.81 (0.77–0.85) <0.001

achycardia; VT, ventricular tachycardia.

Fig. 13. Kaplan-Meier estimated rates ofthe first occurrence of an episode of ven-tricular tachycardia lasting at least8 beats. The incidence of ventriculartachycardia was significantly lower inpatients treated with ranolazine versusplacebo at 24 hours after randomization(2.3% versus 3.4%; relative risk [RR],0.67; 95% CI, 0.50–0.90; P 5 .008) and48 hours (3.1% versus 4.7%; RR, 0.65;95% CI, 0.51–0.84; P < .001). (From SciricaBM, Morrow DA, Hod H, et al. Effect ofranolazine, an antianginal agent withnovel electrophysiological properties,on the incidence of arrhythmias inpatients with non ST-segment elevationACS: results from the Metabolic Effi-

ciency With Ranolazine for Less Ischemia in Non ST-Elevation Acute Coronary Syndrome Thrombolysis in Myocar-dial Infarction 36 (MERLIN-TIMI 36) randomized controlled trial. Circulation 2007;116:1650; with permission.)

Stone612

rat hearts ranolazine prevents the left ventricularsystolic and diastolic dysfunction associated withexposure to ischemia (Fig. 14).4 Similarly, isolatedrat hearts exposed to hydrogen peroxide, the pri-mary reactive oxygen species associated with det-rimental oxidative stress, develop immediatediastolic dysfunction, which can be amelioratedby treatment with ranolazine.19

In intact animal models of heart failure ranola-zine improves myocardial function. Sabbah andcolleagues created chronic heart failure in dogsby intracoronary microembolizations (mean leftventricular ejection fraction 27%) and then admin-istered ranolazine intravenously with a bolus andinfusion (1.0 mg/kg/h).20 Ranolazine significantlyincreased the ejection fraction (27% to 36%,

Fig.14. Ranolazine prevents left ventricular systolic and diaLangendorff perfused hearts. (From Belardinelli L, Antzeltent) sodium current: a potential drug target to reduce iits detrimental effects on cardiomyocyte function. Europe

P 5 .0001), the peak left ventricle 1dP/dt (1712to 1900 mm Hg/s, P 5 .001), and stroke volume(20 to 26 mL, P 5 .0001) without affecting heartrate or systemic pressure. Using this same model,these investigators subsequently demonstratedthat both ranolazine and dobutamine infusionsincreased left ventricular ejection fraction, strokevolume, cardiac output, and peak 1dP/dt, withoutaffecting heart rate or systolic pressure, but thatthe improvement from ranolazine, in comparisonto dobutamine, was related to an increase in leftventricular mechanical efficiency and not to anincrease in coronary blood flow or myocardial O2

consumption.21 Indices of diastolic dysfunctionwere not assessed in these studies. In contrastto these studies, Aaker and colleagues created

stolic dysfunction caused by ischemia in rabbit isolatedevitch C, Fraser H. Inhibition of late (sustained/persis-ntracellular sodium-dependent calcium overload andan Heart Journal 2004;6:16; with permission.)

Ranolazine: New Paradigm for Management 613

chronic heart failure in rats by surgically inducingan MI, and then administered ranolazine50 mg/kg twice a day.22 They observed that rano-lazine did not increase the endurance capacity inthese animals, but the doses used in this studywere almost 10 times the usual dose in humans.

Preliminary studies in humans suggest thatranolazine may be of clinical usefulness in themanagement of patients who have diastolic dys-function associated with ischemic cardiomyopa-thy. Hayashida and colleagues23 administeredintravenous ranolazine 200 or 500 mg/kg to15 patients who had previous transmural MI inwhom regional left ventricular segments wereclassified as either normal, ischemia, or infarcted.Administration of ranolazine significantlyincreased the regional peak filling rate and theregional wall lengthening during the isovolumicrelaxation period in the ischemic segments(P < .05), indicating an improvement of regionaldiastolic function, without significant effect onthe infarcted segments. Early preliminary experi-ence suggested that ranolazine immediate-releaseformulation improved the peak filling rate asassessed by echo Doppler analysis of the left ven-tricular filling dynamics.24 Similarly, intravenousadministration of ranolazine to 15 patients whohad ischemic cardiomyopathy led to a significantdownward shift of the pressure–volume relation-ship during diastole accompanied by a reductionin mean diastolic wall stress and increase in end-diastolic volume.25 A recent preliminary studyinvestigating the proof-of-concept of the effectsof ranolazine in patients who had a documentedgenetic defect in the late sodium channel, thehereditary long QT syndrome LQT3-deltaKPQ,found that intravenous ranolazine shortened theprolonged QTc and significantly improved the as-sociated diastolic dysfunction, as assessed bythe left ventricular isovolumic relaxation time andthe mitral E-wave velocity.26

Further studies in humans investigating the roleof ranolazine in treating diastolic dysfunction areongoing and the results are awaited with greatinterest.

SUMMARY

Ranolazine is a new compound that has beenapproved by the FDA for use in patients whohave chronic stable angina refractory to conven-tional antianginal medications. Its mechanism ofaction does not depend on lowering determinantsof myocardial O2 demand, which is the mechanismused by conventional anti-ischemic medications,but instead it prevents the pathologic persistentopening of the late INa current, which occurs

when the myocardium is exposed to ischemia,heart failure, and oxidative stress. Ranolazinethereby prevents the intracellular sodium and sub-sequent calcium overload that occurs in these dis-orders, and the associated myocardial metabolic,electrophysiologic, and mechanical dysfunction.Ranolazine consequently improves diastolic andsystolic left ventricular function and preservesmyocardial perfusion.

Ranolazine is effective as monotherapy forpatients who have stable angina and also effectiveas part of a combination regimen. In non–STelevation ACS it reduces recurrent ischemia andventricular and atrial arrhythmias, but has no effecton mortality or development of MI.

In animal models of heart failure and in prelimi-nary studies in humans, ranolazine improvesdiastolic and systolic dysfunction.

More studies are needed to evaluate the role ofranolazine as primary therapy for myocardialdiastolic and systolic dysfunction and ventricularand atrial arrhythmias.

REFERENCES

1. Gibbons RJ, Abrams J, Chatterjee K, et al. ACC/

AHA 2002 guideline update for the management of

patients with chronic stable angina—summary

article: a report of the American College of Cardiol-

ogy/American Heart Association Task Force on prac-

tice guidelines (Committee on the Management of

Patients With Chronic Stable Angina). J Am Coll

Cardiol 2003;41:159–68.

2. McCormack JG, Barr RL, Wolff AA, et al. Ranolazine

stimulates glucose oxidation in normoxic, ischemic,

and reperfused ischemic rat hearts. Circulation

1996;93:135–42.

3. MacInnes A, Fairman DA, Binding P, et al. The

antianginal agent trimetazidine does not exert its

functional benefit via inhibition of mitochondrial

long-chain 3-ketoacyl coenzyme A thiolase. Circ

Res 2003;93:e26–32.

4. Belardinelli L, Antzelevitch C, Fraser H. Inhibition of

late (sustained/persistent) sodium current: a poten-

tial drug target to reduce intracellular sodium-

dependent calcium overload and its detrimental

effects on cardiomyocyte function. Eur Heart J

2004;6:13–7.

5. Undrovinas AI, Belardinelli L, Undrovinas NA, et al.

Ranolazine improves abnormal repolarization and

contraction in left ventricular myocytes of dogs with

heart failure by inhibiting late sodium current.

J Cardiovasc Electrophysiol 2006;17(Suppl 1):

S169–77.

6. Antzelevitch C, Belardinelli L, Zygmunt AC, et al.

Electrophysiological effects of ranolazine, a novel

Stone614

antianginal agent with antiarrhythmic properties.

Circulation 2004;110:904–10.

7. Belardinelli L, Shryock JC, Fraser H. The mechanism

of ranolazine action to reduce ischemia-induced di-

astolic dysfunction. Eur Heart J 2006;8:A10–3.

8. Song Y, Shryock JC, Wu L, et al. Antagonism by

ranolazine of the pro-arrhythmic effects of increasing

late INa in guinea pig ventricular myocytes. J Cardi-

ovasc Pharmacol 2004;44:192–9.

9. Chaitman BR. Ranolazine for the treatment of

chronic angina and potential use in other cardiovas-

cular conditions. Circulation 2006;113:2462–72.

10. Stone PH, Chaitman BR, Koren A, et al. Effects of

ranolazine as monotherapy and combination ther-

apy on rate pressure product at rest and during

exercise: results from the MARISA and CARISA

trials. Circulation 2006;114(Suppl II):II-715.

11. Rousseau MF, Pouleur H, Cocco G, et al. Compara-

tive efficacy of ranolazine versus atenolol for chronic

angina pectoris. Am J Cardiol 2005;95:311–6.

12. Chaitman BR, Skettino SL, Parker JO, et al. Anti-

ischemic effects and long-term survival during rano-

lazine monotherapy in patients with chronic severe

angina. J Am Coll Cardiol 2004;43:1375–82.

13. Chaitman BR, Pepine CJ, Parker JO, et al. Effects of

ranolazine with atenolol, amlodipine, or diltiazem on

exercise tolerance and angina frequency in patients

with severe chronic angina: a randomized controlled

trial. JAMA 2004;291:309–16.

14. Stone PH, Gratsiansky NA, Blokhin A, et al. Antiangi-

nal efficacy of ranolazine when added to treatment

with amlodipine: the ERICA (Efficacy of Ranolazine

in Chronic Angina) trial. J Am Coll Cardiol 2006;48:

566–75.

15. Morrow DA, Scirica BM, Karwatowska-Prokopczuk E,

et al. Effects of ranolazine on recurrent cardiovascular

events in patients with non-ST-elevation acute coro-

nary syndromes: the MERLIN-TIMI 36 randomized

trial. JAMA 2007;297:1775–83.

16. Scirica BM, Morrow DA, Hod H, et al. Effect of rano-

lazine, an antianginal agent with novel electrophysi-

ological properties, on the incidence of arrhythmias

in patients with non ST-segment elevation acute

coronary syndrome: results from the Metabolic

Efficiency With Ranolazine for Less Ischemia in

Non ST-Elevation Acute Coronary Syndrome Throm-

bolysis in Myocardial Infarction 36 (MERLIN-TIMI 36)

randomized controlled trial. Circulation 2007;116:

1647–52.

17. Morrow DA, Scirica BM, Sabatine MS, et al. B-type

natriuretic peptide and the effect of ranolazine in

patients with non-ST elevation acute coronary syn-

dromes in the MERLIN-TIMI 36 Trial. Circulation

2007;116(Suppl II):II-382.

18. Sossalla S, Wagner S, Rasenack EC, et al. Ranola-

zine improves diastolic dysfunction in isolated myo-

cardium from failing human hearts—role of late

sodium current and intracellular ion accumulation.

J Mol Cell Cardiol 2008;45:32–43.

19. Matsumura H, Hara A, Hashizume H, et al. Protec-

tive effects of ranolazine, a novel anti-ischemic

drug, on the hydrogen peroxide-induced derange-

ments in isolated, perfused rat heart: comparison

with dichloroacetate. Jpn J Pharmacol 1998;77:

31–9.

20. Sabbah HN, Chandler MP, Mishima T, et al. Ranola-

zine, a partial fatty acid oxidation (pFOX) inhibitor,

improves left ventricular function in dogs with

chronic heart failure. J Card Fail 2002;8:416–22.

21. Chandler MP, Stanley WC, Morita H, et al. Short-term

treatment with ranolazine improves mechanical effi-

ciency in dogs with chronic heart failure. Circ Res

2002;91:278–80.

22. Aaker A, McCormack JG, Hirai T, et al. Effects of

ranolazine on the exercise capacity of rats with

chronic heart failure induced by myocardial infarc-

tion. J Cardiovasc Pharmacol 1996;28:353–62.

23. Hayashida W, van Eyll C, Rousseau MF, et al. Effects

of ranolazine on left ventricular regional diastolic

function in patients with ischemic heart disease.

Cardiovasc Drugs Ther 1994;8:741–7.

24. Rousseau MF, Cocco G, Bouvy T, et al. Effects of

a novel metabolic modulator, ranolazine, on exercise

tolernace and left ventricular filling dynamics in pa-

tients with angina pectoris. Circulation 1992;

86(Suppl I):I-714.

25. Rousseau MF, Van Eyll C, Van Mechelen HV, et al.

Novel metabolic modulator ranolazine selectively

improves diastolic function in heart failure. Circula-

tion 1992;86(Suppl I):I-375.

26. Moss A, Zareba WZ, Schwarz KQ, et al. Ranolazine

shortens repolarization and improves myocardial

relaxation in patients with type-3 long QT syndrome.

J Am Coll Cardiol 2008;51(Suppl A):A15.