New Drug Class

Ranolazine for chronic stable angina

David T Nash, Stephen D Nash

Ranolazine is a new and unique antianginal drug that has been approved for the treatment of chronic stable angina Lancet 2008; 372: 1335–41
pectoris. The drug is administered as a sustained-release formulation. Although the drug’s mechanism of action has Syracuse Preventive
not been fully elucidated, current thinking is that ranolazine, a selective inhibitor of late sodium influx, attenuates Cardiology, Syracuse, NY, USA
(Prof D T Nash MD, S D Nash MD)
the abnormalities of ventricular repolarisation and contractility associated with ischaemia. Three randomised trials
Correspondence to:
have shown efficacy for ranolazine in increasing exercise testing or reducing anginal episodes or use of glyceryl
Prof David T Nash, Syracuse
trinitrate. Side-effects include dizziness, constipation, nausea, and the potential for prolongation of the QTc interval. Preventive Cardiology,
Ranolazine seems to be a safe addition to current traditional drugs for chronic stable angina, especially in aggressive 600 East Genesee Street,
multidrug regimens. Syracuse, NY 13202, USA
Davidtnash@aol.com

Introduction Structure, pharmacokinetics, drug–drug

Despite advances in the diagnosis and treatment of interactions, and contraindications
cardiovascular disease, and substantial decreases in Ranolazine is N-(2,6-dimethylphenyl)-4(2-hydroxy-3-[2-
mortality from this disease, ischaemic heart disease methoxyphenoxy]-propyl)-1-piperazine acetamide dihydro-
continues to be the leading cause of death in the USA.1 chloride (figure 1).5 The drug was patented in 1986 and
Chronic stable angina pectoris, one of the most common approved in early 2006 for patients who remain
symptoms of ischaemic heart disease, has been well symptomatic while on standard antianginal therapy. In
described, starting with a remarkably accurate report by the USA, the tradename is Ranexa.
William Heberden in 1772.2 The prevalence of chronic Ranolazine is available as film-coated sustained-release
stable angina in the USA is about 9·1 million; in a nation 500 mg tablets. The elimination half-life for the
of more than 300 million, that is about 3% of the total extended-release tablet is about 7 h. Steady-state
population.1,3 The annual incidence of clinically identified concentrations are generally achieved within 3 days of
chronic stable angina in the USA is 213 per 100 000 adults 500–1000 mg twice daily.6,7 The drug is metabolised by
older than 30 years. The annual incidence of chronic cytochrome P450 (CYP3A4) enzymes and to a lesser
stable angina in the USA is a function of ageing and extent by CYP2D6, with 5% excreted unchanged by
varies with ethnic origin and sex. The annual rate the kidney. The major metabolites are formed by
per 1000 white men at ages 65–74, 78–84, and more than N-dealkylation of the piperidine ring, O-dearylation of
85 years is 28·3, 36·3, and 33·0, respectively; for white the methoxyphenoxy moiety, hydrolysis of the amide
women, the figures are 14·1, 20·0, and 22·9. For black group, oxygenation at four sites in the parent molecule,
men, the numbers are 22·4, 33·8, and 35·9, respectively; and conjugation with glucuronide.7 Ranolazine is a weak
and for black women, they are 15·3, 23·6, and 35·9. inhibitor of CYP3A4 and CYP2D6.6,7
There are 30 patients with chronic stable angina for every Although ranolazine is well tolerated by patients with
patient who is admitted with an acute myocardial moderate hepatic impairment, pharmacokinetic variables
infarction.3 The incidence of chronic stable angina in such as maximum plasma concentration are increased
Finland at health clinics and in the private sector has compared with those in healthy individuals. In hepatic
been reported as an age-standardised annual incidence impairment, the slope of the relation between QT
per 100 population at ages 45–89 years was 2·03 in men prolongation and plasma concentration of ranolazine is
and 1·89 in women.4 steeper.8 Ranolazine clearances are reduced in renal
Chronic stable angina describes those patients who insufficiency. The maximum plasma concentration at
still have anginal symptoms and objective evidence of steady state is 1·7–2-fold greater in patients with
ischaemia despite the best medical therapy. The standard
of care for such patients should include some or all of
the following, depending on individual clinical circum- Search strategy and selection criteria
stances: oral nitrates and sublingual glyceryl trinitrate, a We searched sources including PubMed, EmBase, Google,
β blocker that is appropriate for the patient, calcium- and Scopus for the past 5 years, for papers in English. The
channel blockers, statins, aspirin, a lipid-modifying drug last search was in June, 2008. The search terms we used
with a weight-modification and lipid-lowering diet, were: “ranolazine”, “reviews”, “pharmacology”, “randomised
appropriate therapy for hypertension and diabetes controlled trials”, “meta-analysis”, “systematic reviews”,
mellitus, and an exercise regimen suited to the patients’ “clinical conference”, and “practice guidelines”. We checked
abilities, needs, and goals, as well as the complete reference lists of papers we found. For additional
elimination of all tobacco products. Ranolazine is a new references, we contacted two of the researchers in
antianginal drug with some unique properties, and is ranolazine studies. When possible we selected randomised
now available for symptomatic relief in patients with trials for efficacy.
chronic stable angina.

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 New Drug Class

Mechanism of action
OH
OCH3 Although early hypotheses suggested that ranolazine
H acted partly by reducing the oxidation of fatty acids, these
N O
N N effects were observed at concentrations well in excess of
therapeutic plasma levels in human clinical trials.12
O Although the antianginal mechanism of ranolazine’s
activity has not been not fully elucidated, there are clear
Figure 1: Structural formula of ranolazine relations between sodium shifts and intracellular calcium,
because the rise in sodium associated with ischaemia
A B increases intracellular calcium. Electrical excitement
Sodium current (nA) 0 0 causes sodium ions to enter cardiac cells through sodium
channels in the cell membrane. This passage of sodium
ions into the myocardial cell triggers a rapid depolarisation
Late Late
(upstroke) of the action potential. Sodium-channel
openings are very brief and, after opening, the channels
inactivate rapidly; on repolarisation, sodium channels are
Peak Peak
transformed from an inactive to a resting state.13
Ischaemia is associated with disruption in cellular
sodium and calcium homoeostasis. Sodium overload
may result from decreased efflux and increased influx
during ischaemia, with greater sodium accumulation
as the duration of ischaemia lengthens. The result is
an increase in intracellular calcium through the
Action potential (mV)
sodium–calcium exchanger. Failure to maintain intra-
Twitch
cellular homoeostasis of both sodium and calcium leads
Figure 2: Schematic representation of slow sodium current
to electrical instability, arrhythmia, and mechanical
(A) normal. (B) increased late sodium channel. dysfunction (reduced contractility, increased diastolic
tension) and mitochondrial dysfunction with decreased
moderate-to-severe renal insufficiency (<30 mL/min ATP formation and cell injury.14–16 Cardiac abnormalities
creatinine clearance), which results in substantial are associated with increased late influx of sodium, which
increases in the maximum plasma concentration from contributes to the dysregulation of ion homoeostasis and
0–12 h (area under the curve) compared with the area causes electrical and contractile dysfunction (figure 2).17
under the curve in healthy individuals (>81 mL/min).9 Although its mechanism of action in angina remains
Ranolazine concentrations are not affected by food unclear, ranolazine selectively inhibits late sodium influx
intake, and oral bioavailability is about 30–55%. and attenuates the abnormalities of ventricular
Ranolazine’s pharmacokinetics is unaffected by sex, repolarisation and contractility associated with ischae-
diabetes mellitus or congestive heart failure.6,10 mia.17 The mechanisms by which late sodium influx
How various drugs interact with ranolazine has been contributes to ischaemia and the extent to which it
studied.10 Co-administration of ketoconazole, an inhi- modifies calcium overload require further investigation.
bitor of CYP3A, increases plasma concentrations of
ranolazine. Diltiazem 60 mg three times a day for 7 days Efficacy
reduces the oral clearance of ranolazine and inhibits its Immediate-release formulation
metabolism. Simvastatin does not affect ranolazine An early study examined an immediate-release form of
levels, but ranolazine increases the area under the curve ranolazine at moderately low doses.18 This randomised,
and maximum concentration of simvastatin about double-blind, placebo-controlled crossover trial followed
two-fold.10 Ranolazine increases digoxin concentrations up just over 300 patients with chronic stable angina while
about 1·5-fold at peak ranolazine levels. Clinical they withdrew from at least one other antianginal drug
myositis or raised liver-function tests have not been and were then treated with ranolazine 400 mg twice daily,
seen in patients treated with a statin and ranolazine. 400 mg thrice daily, or 267 mg thrice daily, all compared
Verapamil (>360 mg daily) is a moderate CYP3A4 with placebo. Exercise tolerance was measured and the
inhibitor that can increase the absorption of ranolazine total duration of exercise increased. However, the
and lead to a 2·3-fold increase in plasma concentrations immediate-release formulation did not provide
of ranolazine.6,8–10 continuous protection, and only provided short-term
Ranolazine is contraindicated in patients with pre- improvements in exercise duration, time to 1-mm
existing QTc prolongation, who have hepatic or renal ST-segment depression, and time to onset of angina.
impairment, or who are already taking drugs that A study of immediate-release ranolazine versus atenolol
prolong the QTc, or are potent CYP3 inhibitors.10,11 in chronic angina was completed in nine centres in

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 New Drug Class

Canada and Europe in patients with chronic stable angina 500 mg, 1000 mg, or 1500 mg twice daily; all interventions
and documented ST-depression on treadmill testing.19 In were given for a week. The primary endpoint was total
this study, 154 patients discontinued β-blocker therapy exercise duration (at 12 h; ie, at trough concentrations).
during a single-blind washout of 7–10 days, and were Secondary endpoints included time to the onset of angina
randomised to immediate-release ranolazine 400 mg and time to 1-mm ST-segment depression at trough. In
three times a day, 100 mg atenolol daily, or placebo, each the 175 patients with efficacy data with ranolazine at
administered in a three-period crossover design. The 500 mg, 1000 mg, or 1500 mg, exercise duration was 24 s,
primary endpoint was time to onset of angina. Secondary 34 s, and 46 s longer on average than with placebo,
endpoints included time to 1-mm ST-segment depression respectively (all statistically significantly different from
and total exercise time. Patients on ranolazine had, on placebo). Statistically significantly dose-related increases
average, a significantly longer time to angina onset in time to 1-mm ST-segment depression were also found.
during ranolazine and atenolol therapy than during This study thus suggested the antianginal efficacy of
placebo therapy (mean difference 51·0 s, 95% CI ranolazine as monotherapy.
34·2–67·8 s for ranolazine vs placebo). Mean time to CARISA (Combination Assessment of Ranolazine in
angina onset was longer with ranolazine than with Stable Angina) was a double-blind parallel-group trial in
atenolol but the difference was not statistically significant which 823 patients with chronic stable angina who were
(11·4 s, 5·4–28·2 s). already on standard doses of atenolol, amlodipine, or
diltiazem.21 The patients were randomly assigned to twice
Sustained-release formulation daily placebo, or 750 mg or 1000 mg sustained-release
There have been three randomised trials of sustained- ranolazine for 12 weeks. All patients had coronary artery
release ranolazine in chronic stable angina (table). The disease, at least a 3-month history of exertional angina,
Monotherapy Assessment of Ranolazine In Stable reproducible ischaemic ST-segment depression, and
Angina trial (MARISA) was a double-blind crossover limited exercise capacity on treadmill testing. The
study in 191 patients.20 The patients had angina-limited primary endpoint was treadmill exercise duration at
treadmill tests, discontinued antianginal therapy (except trough (12 h). Secondary endpoints included exercise
for sublingual glyceryl trinitrate as needed), and were duration at 4 h after dosing, and times to angina and to
randomised to placebo or sustained-release ranolazine at 1-mm ST segment depression at trough (12 h). Compared

MARISA20 CARISA21 ERICA22 MERLIN-TIMI 3623

Number 175 823 565 6560
analysed
Dose 500, 1000, or 1500 mg ranolazine twice daily vs 750 mg or 1000 mg 1000 mg ranolazine twice daily vs Ranolazine 1000 mg twice daily vs placebo
placebo for four 1-week periods; 168 patients ranolazine twice daily vs placebo
completed all four crossover periods placebo
Follow-up 1 and 2 years 12 weeks initially, long term 6 weeks 348 days
1 and 2 years
Primary Dose-related increase in exercise duration at Exercise duration at trough: Frequency of angina episodes: Composite of cardiovascular death, myocardial
endpoint trough: 23·7 s at 750 mg, 33·7 s at 1000 mg, difference from placebo ranolazine reduced episodes by 2·9 vs infarction, or recurrent ischaemia: 696 patients
and 45·9 s at 1500 mg (vs placebo, p<0·003, 23·7 s, 24·0 s (p=0·03 for 3·3 with placebo (p=0·028) (21·8%) on ranolazine vs 753 patients on placebo
p<0·001, p<0·001) both doses) (23·5%) (hazard ratio 0·92, 95% CI 0·83–1·02)
Secondary Time to onset of angina: 27·0, 45·9, and 59·6 s Time to angina: 30 vs 26 s for Tablets per week of glyceryl trinitrate: Syncope: ranolazine, 109 cases vs placebo, 75 cases;
endpoints at 500, 100, and 1500 mg, respectively (vs placebo (p<0·01) 2·00 ranolazine vs 2·68 on placebo QTC prolongation: ranolazine, 0·9% vs 0·3%, placebo;
placebo, p=0·005, p<0·001, p<0·001) Reduced angina episodes by (p=0·014) Recurrent ischaemia: ranolazine, 430 (13·9)% vs
Time to 1-mm ST-segment depression: 27·6, 1 per week: 750 mg, placebo, 494 (16·1)% (hazard ratio 0·87, 0·76–0·99)
44·5, and 64·6 s, respectively (all p<0·001 vs (p=0·006); 100 mg
placebo) (p<0·001)
Additional 1-year follow-up survival, for 1500 mg: 96·3% Survival of 750 patients on .. No difference in mortality: ranolazine 172 vs placebo
comments (95% CI 93·0–99·5%) ranolazine (both doses), 175 (hazard ratio 0·99, 0·80–1·22)
2–year follow-up survival: 93·6% (89·3–98·0%) 1 year: 98·4% (97·4–99.5%);
2 year: 95·9% (94 0–97·7%)
Side-effects 1500 mg ranolazine vs placebo: dizziness: Ranolazine vs placebo: No torsade de pointes 1 case of torsade de pointes in both ranolazine and
12·3% vs 1·0%; nausea: 8·6% vs 0%; asthenia: constipation 7·3% vs 0·7%; All vs placebo—constipation: 8·9% vs placebo groups
6·4% vs 2·5% dizziness 6·9% vs 1·9%; 1·8%; peripheral oedema: 5·7% vs 2·8%; Ranolazine vs placebo—dizziness 13% vs 0·7%;
Syncope was reported in 3 patients, all at asthenia 4·7% vs 2·2%; dizziness: 3·9% vs 2·5%; cardiovascular: nausea: 9% vs 6%; constipation: 9% vs 6%
1500 mg twice daily syncope 5 vs 0 5·7% vs 7·8%; myocardial infarction and
congestive heart failure: 0·4% vs 0·7%;
ventricular extrasystoles: 1·1% vs 1·1%;
first-degree atrioventricular block: 0%
vs 1·1%

Table: Efficacy and safety of sustained-release ranolazine in three randomised trials in chronic stable angina and randomised trial in non-ST-elevation acute coronary syndrome
(MERLIN-TIMI 36)

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 New Drug Class

with placebo, there was a statistically significantly men, at some point in elderly populations, coronary heart
increase from baseline in exercise duration in both drug disease in women may become as prevalent as or more
groups of 24 s (table). Time to angina and ischaemia also common than in men.24,25
increased. Ranolazine also reduced anginal episodes, on There is no clear generally agreed explanation for this
average by a mean of one attack per week, compared with higher prevalence in women. The diagnosis of chronic
placebo. Thus CARISA suggested the value of ranolazine stable angina implies an adverse prognosis in both sexes
in improving exercise duration when used as add-on but the outlook is less sanguine for women, possibly
therapy. related to less aggressive evaluation and treatment.26
The ERICA (Efficacy of Ranolazine in Chronic Angina) Women are more likely than men to develop chest pain
trial examined the efficacy of ranolazine in patients with and curtail their activities,27 and women are more likely to
persistent symptoms despite treatment with 10 mg report worse health-related quality-of-life outcomes than
amlodipine.22 Inclusion criteria included documented men.27,28
coronary artery stenosis of 60% of at least one major A review by sex of some of the trials, including
coronary artery, a stress-induced perfusion defect visible MARISA, ERICA, and CARISA, examined data from
on imaging, chronic stable angina for at least 3 months, more than 1700 patients with stable angina.29 Only
and at least three episodes of angina a week during a 412 of the participants were women: selection bias may
2-week qualification period while on amlodipine. contribute to this reduced recruitment. In most of the
565 patients were randomised: 281 to ranolazine, and trials men predominated; research sites included the
284 to placebo. The primary endpoint was self-reported Czech Republic, and Poland, where most of the patients
anginal episodes during the 6-week double-blind were male, and efficacy measurements were completely
treatment phase. There was, on average, one fewer available in only 202. Women showed less improvement
episode of angina per week in the ranolazine group than than men in exercise testing in these studies, but
in the placebo group (table). The secondary endpoints ranolazine decreased their angina frequency and use
were average weekly consumption of glyceryl trinitrate, of glyceryl trinitrate, and significantly increased the
and anginal descriptions, during the 6-week double-blind time to angina by 55 s (p=0·035) and time to 1-mm
full-dose treatment period as well as patients’ perception ST-segment depression by 50 s (p=0·004) compared
of physical limitation and satisfaction with treatment. with placebo. What is apparent from these randomised
Consumption of glyceryl trinitrate was reduced on trials is that ranolazine reduces angina and increases
average by 0·9 tablets a week. the time to 1-mm ST-segment depression in female
Ranolazine has also been studied in patients with patients with chronic stable angina.29
non-ST-elevation acute coronary syndrome. Although
this is an acute condition, such a study permits a Side-effects and safety
broader view of the safety and efficacy of the drug. Adverse events during MARISA were noted in 26 (14·5%)
The MERLIN-TIMI 36 double-blind trial enrolled patients on placebo, compared with 28 (15·5%),
6560 patients who were in hospital with non-ST-elevation 37 (20·6%), and 62 (33·2%) patients on ranolazine
acute coronary syndrome.23 Patients were randomised, 500 mg, 1000 mg, or 1500 mg twice daily, respectively.20
within 48 h of symptoms starting, to placebo or At the 1500 mg dose, the most common adverse events
ranolazine, initially intravenously and then orally. The reported were dizziness (22 [12·3%] patients), nausea
oral dose was 1000 mg twice daily. The primary endpoint (16 [8·6%]), asthenia (11 [6·4%]), and constipation
was a composite of cardiovascular death, myocardial (8 [4·3%], table). Over the three doses, asthenia, headache,
infarction, and recurrent ischaemia. Safety endpoints dyspepsia, and abdominal pain occurred more frequently
included all-cause deaths, hospital re-admissions, and than with placebo. Three patients had syncope, all at a
symptomatic documented arrhythmias. After a mean dose of 1500 mg twice daily.
follow-up of 348 days, the primary endpoint occurred in In CARISA, five patients, who were aged more than
23·5% of the placebo group and 21·8% of the ranolazine 65 years and were all on 1000 mg ranolazine, had syncope.
group (hazard ratio 0·92, 95% CI 0·83–1·02). There None of these cases were associated with torsade de
were also no statistically significant differences in the pointes.
major secondary endpoints (table). No case of syncope was reported in ERICA at a
ranolazine dose below 1000 mg twice daily. Side-effects of
Sex difference in efficacy ranolazine in ERICA included: constipation (8·9% of
It is probably only a coincidence that the three major patients in the ranolazine group vs 1·8% in the placebo
ranolazine trials in chronic stable angina used female group), dizziness (3·9% vs 2·5%), nausea (2·8% vs
names as the trial acronyms, but there is a certain irony 0·7%), and headache (2·8% vs 2·5%) (table).22 There
here. Most publications report that angina pectoris is a were no significant laboratory or physical abnormalities.
more common manifestation in men than in women, No cases of torsade de pointes were reported. Ranolazine
but a few report the reverse. Selection bias may account was well tolerated, and only 1% of the trial patients
for these differences. Because women live longer than withdrew because of a drug-related adverse event. Seven

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patients—three on ranolazine, four on placebo— QTc prolongation

discontinued the study because of adverse events. Although rare, many drugs, including those prescribed
In MERLIN-TIMI 36, a prespecified set of arrhythmias for non-cardiac indications, can induce electrophysio-
was assessed by a blinded core laboratory.23,30 Of the total logical changes that trigger a malignant polymorphic
group, 6351 (97%) patients had continuous ECG ventricular tachyarrhythmia known as torsade de pointes.
recordings that could be evaluated for arrhythmias. Prolongation of the QT interval of the ECG is associated
Treatment with ranolazine resulted in fewer patients with increased risk of torsade de pointes. Ranolazine can
having ventricular tachycardia lasting for more than increase the duration of the action potential and the QT
eight beats (166 [5·3%] on ranolazine vs 265 [8·3%] on interval.35
placebo, p<0·001), supraventricular tachycardia Although prolongation of the QT interval is apparent
(1413 [44·7%] vs 1752 [55·0%], p<0·001), or new-onset on electronic analysis of population-wide ECGs, the
atrial fibrillation (55 [1·7%] vs 75 [2·4%], p=0·08). average prolongation (seen with 1000 mg ranolazine twice
Additionally, pauses of more than 3 s were less frequent a day) might be difficult to pick up in view of the normal
with ranolazine (97 [3·1%] vs 136 [4·3%], p=0·01). intra-patient variability in the QT interval of between 30
MERLIN-TIMI 36 accessed a new indication for and 60 ms. Use of ranolazine has been associated with
ranolazine: patients with acute coronary syndrome. The measurable prolongation of the QTc interval, but an
study showed a reduction in recurrent ischaemia and in increase in significant arrhythmias has not been seen.20,21
ventricular and supraventricular arrhythmias in Safety was also examined in the double-blind
long-term therapy, and provided additional evidence of placebo-controlled trials, including MARISA, CARISA,
safety in these high-risk patients. and ERICA as well as MERLIN-TIMI 36.20–23
The ROLE (Ranolazine Open Label Experience) However, ranolazine also reduces the late sodium
programme consisted of patients who had completed the current, a depolarising current that contributes to the
MARISA and CARISA trials and were willing to prolongation of the plateau phase of the ventricular action
participate in an open-label extension.31 All the ROLE potential. A study in isolated guineapig hearts measured
participants had been characterised as having severe the effects of ranolazine alone and in the presence of
functional limitations due to angina, and were assigned a anemone toxin, whose action mimics the sodium
Duke treadmill score.32 The Duke score permitted a channelopathy associated with long QTc syndrome.
measurement by which the participants could be Although ranolazine alone prolonged the duration of the
compared with expected survival rates.33 action potential, it reduced ventricular arrhythmias caused
ROLE participants were recruited in 123 outpatient sites by agents that increased the late sodium current.36,37
in 12 nations. Investigators could titrate the ranolazine
dose between 500 and 2000 mg twice daily depending on Conclusions
clinical responses during regular clinic visits. 746 patients The beneficial effects of adding ranolazine to previously
entered the ROLE programme: 143 of the 168 patients available standard antianginal therapy have been shown
who had completed MARISA, and 603 of the 731 patients in the ERICA trial in combination with amlodipine
who had completed CARISA. Most were white men, and baseline therapy versus ranolazine or placebo. However,
had received ranolazine for an average of 2·8 years. there have not been major trials testing various
Adverse events accounted for about half of the combination therapies with an aim to alleviate angina to
discontinuations, and elective withdrawal or death the point of patients’ tolerance to treatment. Despite
accounted for most of the remainder. The increase in treatment with conventional agents or revascularisation,
discontinuations and elective withdrawals is probably or both, many patients remain symptomatic 1 year after
related to the 2·8 years of follow-up available on the coronary artery bypass grafting or percutaneous coronary
recruited patients in ROLE. The most common symptom intervention, and 25–60% of patients require antianginal
was dizziness (12%) and constipation (10%), generally medication.38,39 Ranolazine may provide an additional
side-effects that are not considered serious, and each led option for such patients.
to a less than a 1% discontinuation rate. Discontinuation Ranolazine is an efficacious new drug for chronic
was more likely in those patients who were older than stable angina. Side-effects include dizziness, consti-
64 years. For older patients compared with middle-aged pation, nausea, and the potential for prolongation of the
individuals (45–64 years), the relative risk of QTc interval. No increase in torsade de pointes has been
discontinuation was 2·32 (95% CI 1·49–3·61, p<0·001). reported. Ranolazine seems to provide a safe addition to
This rate is not unexpected; there is an increased the current traditional drugs used by physicians who
susceptibility to untoward effects with advancing age for treat patients with chronic stable angina and who want
many therapeutic interventions.34 The QTc interval was to treat their patients with an aggressive multidrug
prolonged on average (being 2·4 ms), but sixteen ECG regimen. Many patients treated with combinations of
tracings from the 746 patients showed QTc prolongation drugs, whose angina disappears or becomes minimal
of more than 500 ms. No patient withdrew because of QTc and non-disabling, will be able to avoid or delay
prolongation, and no torsade de pointes was reported. revascularisation without paying a known mortality

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price for their decision. A trial that looks at References

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efficacy in reducing the symptoms of chronic stable 18 Pepine CJ, Wolff AA, on behalf of the Ranolazine Study.
angina.44,45 Combination of such interventions with the A controlled trial with a novel anti-ischemic agent, ranolazine,
in chronic stable angina pectoris that is responsive to conventional
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Conflict of interest statement Assessment of Ranolazine In Stable Angina (MARISA) Trial
DTN has received research support from, been on speakers’ bureau for, investigators. Anti-ischemic effects and long term survival during
or received unrestricted educational grants from: Abbott, AstraZeneca, ranolazine monotherapy in patients with chronic severe angina:
a randomised controlled trial. J Am Coll Cardiol 2004; 43: 1375–82.
Dow, Lilly-Icos, Merck, Parke-Davies, Pfizer, Reliant, Sandoz, Warner
Lambert, and Upjohn. He has also served as a scientific reviewer for the 21 Chaitman BR, Pepine CJ, Parker JO, et al, for The Combination
Assessment of Ranolazine In Stable Angina (CARISA)
not-for-profit Institute for the Study of Aging. SDN declares that he has
investigators. Effects of ranolazine with atenolol, amlodipine, or
no conflict of interest. diltiazem on exercise tolerance and angina frequency in patients
Acknowledgments with severe chronic angina: a randomised controlled trial.
We thank James Capodagli (Health Science Library, SUNY Upstate JAMA 2004; 291: 309–16.
Medical University, Syracuse, NY, USA) for help with the literature 22 Stone PH, Gratsiansky NA, Blokhin A, et al, for the ERICA
search, Jeremy A Nash (Information Technology University of Colorado, Investigators. Antianginal efficacy of ranolazine when added to
Boulder, CO, USA) for organising the table, and Celeste Marx (CVT treatment with amlodipine: the ERICA (Efficacy of Ranolazine in
Chronic Angina) trial. J Am Coll Cardiol 2006; 48: 566–75.
Therapeutics Inc, Palo Alto, CA, USA) for providing the figures.

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