CASE 12-1, QUESTION 8: Are there any dietary patterns that J.P. can adopt that have demonstrated
reductions in cardiovascular end points?
Although the positive effects of lifestyle modifications on cardiovascular risk
factors are well recognized, the effect of specific lifestyle interventions on reducing
hard cardiovascular end points can be underappreciated. The adoption of a healthy
dietary pattern is one such example. Randomized controlled trials have demonstrated
that the adoption of the Mediterranean Diet (diets emphasizing whole grains, fruit,
vegetables, nuts and legumes, moderate dairy intake, moderate amounts of lean
protein, and polyunsaturated fats) reduced the relative risk of MI or cardiac death by
50% to 73% as compared to a diet similar in composition to the AHA Step I diet.
is important to note that in one of these studies, the Lyon Diet Heart Study, the
improvements in cardiovascular morbidity and mortality occurred without significant
changes in the lipid profiles of study subjects.
46 One trial found the Mediterranean
Diet supplemented with either nuts or olive oil reduced cardiovascular events in
patients at high risk of CVD when compared to a low fat diet.
trials demonstrated that patients with a history of MI who increased their intake of
either fatty fish or ingested omega-3 fatty acid fish oil supplements also had
reductions in cardiovascular death and
MI as compared to control patients without dietary intervention.
epidemiologic studies have confirmed the results from randomized controlled trials
showing that adherence to a Mediterranean diet significantly reduces cardiovascular
46 A Mediterranean diet reduces systemic inflammation as
measured by C-reactive protein, reduces the incidence of insulin resistance, and
improves endothelial function. Although a great deal of attention has been directed at
the increased intake of omega-3 polyunsaturated acids (eicosapentaenoic acid and
docosahexaenoic acid derived from fish or α-linoleic acid derived from plants)
being responsible for the observed benefits in each of these trials, multiple dietary
alterations were likely in play. The results should be interpreted as the result of the
adoption of a healthy dietary pattern.
Because oxidation of LDL in the arterial wall is a key step in the atherosclerotic
process, considerable interest exists in the theory that supplementation with high
doses of antioxidants such as vitamin E, vitamin C, and β-carotene might mitigate this
process and slow the progression of atherosclerosis. Early observational studies of
antioxidants seemed to confirm this theory. Multiple large randomized studies,
however, have shown no positive effect from supplemental intake of antioxidants
such as vitamin E on the incidence of cardiovascular outcomes including MI or
1,49 These findings were observed in both primary and secondary prevention of
cardiovascular events. J.P. should be informed that supplemental intake of vitamin E
will not have any positive effect on his CVD.
Interest in the use of supplemental intake of folic acid and B vitamins stems from
their ability to lower homocysteine levels. It is well established that elevated levels
of homocysteine are associated with a higher incidence of CVD.
vitamins has no impact in reducing cardiovascular outcomes such as MI or death
Therefore, similar to the advice for vitamin E, J.P. should be counseled that folic
acid and B vitamin supplementation will not provide any tangible cardiovascular
If so, what education should J.P. receive with regard to the use and storage of SL NTG?
All patients with CAD, especially those with chronic stable angina, should receive
a prescription for SL NTG for the treatment of acute anginal attacks.
to vasodilation of both veins and arteries which reduces myocardial oxygen demand,
thereby relieving angina. Because response to NTG varies among patients, the
dosage should be individualized (Table 12-4). Most patients, however, use a dose of
0.4 mg. The administration of sublingual NTG is also useful in patients who have a
good understanding of what level of exertion produces their chest pain. About 5 to 10
minutes before J.P. is about to undergo heavy exertion, he can take a sublingual NTG
Patient education is a crucial component of ensuring SL NTG is used appropriately
to treat acute anginal attacks. When angina occurs, J.P. should sit down immediately
and utilize his SL NTG. If using tablets, he should place the NTG tablet under his
tongue; he should not swallow it. If using the NTG spray, he should apply the spray
on or under the tongue and not swallow or inhale it. Many patients experience
dizziness and light-headedness, which is minimized by sitting. The onset of action is
within 1 to 2 minutes, and pain usually is relieved within 3 to 5 minutes. If the pain
persists or is unimproved 5 minutes after the first dose of NTG, the patient should
call 9-1-1 as they may be experiencing an MI.
If he needs more than one dose, he can
take a maximum of 1.2 mg in 15 minutes.
The tablets should be dispensed in the original, unopened manufacturer’s container
and stored in the original brown bottle. Because sublingual NTG tablets are
degraded by heat, moisture, and light, they should be stored in a cool, dry place, but
not refrigerated. The bottle should be closed tightly after each opening. Safety caps
should not be used, although patients should be cautioned to keep all medications out
of the reach of children. The cotton plug sometimes is difficult to remove. Therefore,
it should be discarded on initial receipt of the prescription and should not be
replaced. Use of cotton other than that supplied by the manufacturer should be
discouraged because NTG tablets are volatile and are adsorbed by household cotton.
This results in a significant loss in tablet effectiveness. Expiration dating should be
monitored closely, and tablets should be replaced immediately if they are exposed to
excessive light, heat, moisture, or air. Once a container is opened, the tablets should
be used for only a limited time—usually from 6 months to 1 year.
initial option for chronic stable angina in J.P.?
Options for chronic prevention of anginal episodes include β-blockers, CCBs,
long-acting nitrates, and ranolazine. Although each of these options is considered
relatively equivalent in terms of ischemia prevention, current guidelines recommend
that β-blockers should be administered before a nitrate or a CCB when long-term
1,2 β-Blockers are very effective at reducing anginal symptoms
and ischemia, including silent myocardial ischemia.
1,2 β-Blockers also significantly
increase exercise tolerance and time to ST-segment depression during exercise
36 Several cohort and case–control studies have shown that β-blockers
improve clinical outcomes, including reductions in mortality in patients with chronic
In addition, recent evidence indicates that β-blockers may
also slow the progression of atherosclerosis.
In a meta-analysis of clinical trials
that compared the three classes of anti-ischemics, no differences in long-term
mortality were noted. β-Blockers, however, were more effective in lowering the
incidence of anginal episodes.
58 β-Blockers are generally considered the most
effective class of agents at preventing silent myocardial ischemia.
In addition, βblockers clearly lower morbidity and mortality in patients with CAD17,19 and HF.
Overall, the body of literature available supports the recommendation that all
patients with angina should receive a β-blocker as initial therapy unless
CASE 12-1, QUESTION 12: How should therapy with a β-blocker be optimized in J.P.?
All patients receiving antianginal drugs should be monitored for frequency of
angina attacks and SL NTG consumption. Traditionally, clinicians have monitored
the reduction in resting heart rate and have progressively increased the β-blocker
dose until the resting heart rate was 55 or 60 beats/minute.
rate of 78 beats/minute and preserved BP. If J.P. continues to have preserved BP and
his heart rate remains above 55 to 60 beats/minute after the initiation of β-blocker
therapy, a doubling of his dose would be a reasonable increase, with close
monitoring of heart rate and BP. Additional goals with β-blocker therapy include a
maximum heart rate of 100 beats/minute or less with exercise. Resting heart rate less
than 50 beats/minute may be acceptable, provided the patient is asymptomatic and
heart block is not present. Variations in resting heart rate are normal and subject to
the influence of the endogenous sympathetic nervous system and other exogenous
factors, such as drugs, tobacco, and caffeine-containing beverages. β-Blockers with
intrinsic sympathomimetic activity (e.g., pindolol) will not reduce the resting heart
rate as much as β-blockers lacking this activity.
Exercise stress testing is probably the most accurate, but least practical, method of
documenting the adequacy of β-blocker therapy. During an exercise tolerance test, a
β-blocker should substantially increase the time J.P. walks before developing angina.
There also may be a reduction in ST-segment depression during exercise, indicating
less myocardial ischemia. The rate–pressure product probably will be markedly
lower, reflecting a decrease in both heart rate and systolic wall tension.
alternative to conducting a formal stress test is to repeat the physical activity which
produced angina during this hospitalization, namely, walking a few flights of stairs.
history of reactive airway disease such as asthma or PAD?
Although all β-blockers are equally effective in the treatment of angina, the
addition of reactive airway disease or PAD to J.P.’s medical history would pose
several relative contraindications to the use of some β-blockers. The concern directly
relates to the potential for β-blockers to worsen either bronchoconstriction in the
receptors, or worsening vasoconstriction in the
peripheral arteries, again, through blunting vasodilation through β2
Although not absolute contraindications, the presence of these disease states warrants
careful monitoring of β-blocker therapy during initiation and titration.
Cardioselective β-blockers, such as metoprolol, are often considered in patients
with reactive airway disease or PAD with the hope that β2
unaffected. In one meta-analysis, cardioselective β-blockers were better tolerated
than nonselective β-blockers in patients with asthma.
also are less likely to inhibit β2
-mediated vasodilation in the peripheral arterioles.
Therefore, cardioselective β-blockers are preferred over nonselective β-blockers for
patients with PAD and Raynaud disease.
Unfortunately, cardioselectivity is not an all-or-none response; instead, it is a
dose-dependent phenomenon. As the dose is increased, cardioselectivity is lost. The
dose at which cardioselectivity will be lost in any given patient cannot be predicted,
and even a very small dose (e.g., metoprolol 50–100 mg) could cause wheezing.
If β-blocker therapy is to be initiated in a patient with reactive airway disease or
PAD, close monitoring for worsening of symptoms should occur and an alternative
anti-ischemic medication should be used if symptoms worsen.
In the event that β-blocker therapy is not tolerated or considered too risky, initial
therapy with a heart-rate–controlling CCB is the next best option, provided there is
adequate heart rate and BP to tolerate therapy. In patients who already have low
heart rate and/or marginal BP, ranolazine may be considered as an initial option.
Long-acting nitrates are typically reserved for add-on therapy for reasons that will be
Antiplatelet therapy is a cornerstone in the management of a patient with
atherosclerotic vascular disease. Antiplatelet therapy reduces the incidence of CVD
events such as MI, stroke, and death. Although newer antiplatelet options are
available, aspirin is still the first-line choice for patients with atherosclerotic
vascular disease due to well-established efficacy and cost-effectiveness.
The mechanism of action for aspirin’s antiplatelet effect is inhibition of
cyclooxygenase (see Chapter 11, Thrombosis). By acetylating the active site of
cyclooxygenase, aspirin blocks the formation of prostaglandin endoperoxides from
arachidonic acid. This inhibits the formation of both thromboxane and prostacyclin.
is a potent vasoconstrictor and facilitates further activation of
) counterbalances the effect of thromboxane A2
it is a potent inhibitor of platelet aggregation and a vasodilator.
Although it has been theorized that higher doses of aspirin would produce a higher
level of efficacy than low doses, all available literature indicates that low dosages of
aspirin (75–325 mg/day) are as effective as higher dosages (625–1,300 mg/day) in
the treatment of patients with angina.
62 Conversely, as the aspirin dosage increases,
the incidence of adverse effects, especially GI bleeding, increases. Therefore,
current guidelines recommend a daily dosage of 75 to 162 mg orally for the
prevention of MI and death in patients with CAD.
1 Given this information, J.P. should
be advised to take aspirin at a dose of 81 mg/day to maintain efficacy but decrease
CASE 12-1, QUESTION 15: J.P. returns to the hospital with recurrent angina 8 weeks after he was
tablets. How could J.P.’s situation have been avoided?
The β-blocker withdrawal syndrome is a rebound phenomenon resulting from
heightened β-receptor density and sensitivity (i.e., upregulation) subsequent to
receptor blockade. It places patients with CAD at high risk for adverse
cardiovascular events, which may include acute MI and sudden cardiac death. An
“overshoot” in heart rate, as a consequence of sympathoadrenal activity from abrupt
β-blocker withdrawal increases myocardial oxygen demand and platelet aggregation.
Withdrawal syndromes may be less severe in patients taking β-blockers with partial
If β-blockers are to be discontinued, a gradual tapering schedule (preferably for 1–
2 weeks) should be used. Shorter periods for β-blocker withdrawal (e.g., 2–3 days)
have been proposed, although the optimal strategy for discontinuation is not known.
Ensuring that β-blockers are tapered and that the patient is reasonably monitored for
adverse events for the duration of the taper is imperative. Patients should limit
physical activity throughout the β-blocker withdrawal period and seek prompt
medical attention when angina symptoms become apparent. Patients should be
warned not to precipitously discontinue their β-blockers. Failure to renew
prescriptions and financial hardship are common reasons for abrupt discontinuation,
and clinicians need to have sufficient professional rapport with patients to understand
when patients encounter difficulties in obtaining medications.
CASE 12-1, QUESTION 16: J.P. recovers quickly and is discharged from the hospital after 48 hours. He
minutes. He follows a low-cholesterol, no-added-salt diet.
long-acting nitrate the best add-on option for J.P.’s chronic stable angina?
Long-acting nitrates occupy a key role in the prevention of angina of all types. The
goals of therapy are to decrease the number, severity, and duration of J.P.’s anginal
attacks. A CCB could be prescribed for J.P. instead of isosorbide mononitrate
because he has no contraindications to this class of drugs. A CCB would have been a
good alternative if his BP had remained elevated, but for now, J.P.’s BP and pulse
are within a desired range. Nitrates can also affect BP, but will likely do so to a
lesser extent than CCBs. Because sublingual nitrates were well tolerated by J.P., a
long-acting nitrate would be acceptable. If a CCB is considered at this point, a DHP
should be used because they have no effect on heart rate, unlike diltiazem or
verapamil. Lastly, ranolazine would be an option for add-on therapy, especially if
J.P. experiences any adverse hemodynamic effects from either a CCB or long-acting
nitrate. Ultimately, the decision for additional therapy is based on the prescriber’s
personal choice and past experience, as well as the entire spectrum of the patient’s
CASE 12-1, QUESTION 17: WillJ.P. develop tolerance to the long-acting nitrate?
Although not completely understood, several mechanisms of nitrate tolerance have
been proposed, including the increased production of catecholamines, plasma volume
expansion, and activation of the renin-angiotensin-aldosterone system.
All organic nitrates exhibit similar hemodynamic effects through a common
pharmacologic mechanism; yet, the differing pharmacokinetic profiles of the nitrate
delivery systems lead to a variation in the development of tolerance.
formulations (e.g., SL NTG, oral NTG spray, and SL isosorbide dinitrate) are not
likely to induce tolerance given their rapid onset of action and short duration of
effect. Oral nitrates and transdermal products, both having an extended duration of
action, are likely to induce tolerance.
Intermittent application of transdermal NTG can limit tolerance development in
patients with both chronic stable angina and HF. The effects of continuous (24
hours/day) and intermittent (16 hours/day) transdermal NTG (10 mg/day) were
compared in 12 men with chronic stable angina who also were being treated with βblockers or CCB.
66 Nitrate efficacy was maintained with intermittent treatment and an
8-hour nitrate-free interval. Tolerance to the antianginal effects occurred, however,
with continuous treatment. Twelve-hour intermittent patch therapy also prevents
67 The minimal time necessary for a nitrate-free interval is unknown.
Nitrate dosing schedules should be arranged to permit a nitrate-free interval during
which time the patient may receive angina protection from β-blockers, CCBs, or
ranolazine. Most often, this nitrate-free interval is arranged during the night because
angina is more likely to occur during the workday. Patients with nocturnal or early
morning angina should arrange their nitrate-free interval during the day.
Despite the availability of nitrate preparations that can be dosed once or twice a
day (isosorbide mononitrate), oral isosorbide dinitrate is still commonly used in a
variety of settings for the treatment of angina. Isosorbide dinitrate needs to be dosed
three times a day, and presents a challenge in ensuring patients have a nitrate-free
interval. If J.P. were to receive isosorbide dinitrate, he should take his oral nitrate at
7 AM, noon, and 5 PM because his exercise-induced angina is likely to occur during
adequate nitrate-free interval. Because long-acting nitrates must be dosed
intermittently to avoid tolerance, metoprolol therapy will provide J.P. with
indicates that use of long-acting nitrates leads to resistance or tolerance to the effects
CASE 12-1, QUESTION 18: Does isosorbide mononitrate offer any distinct advantages over other nitrate
preparations for angina prophylaxis?
Isosorbide mononitrate is the primary metabolite of isosorbide dinitrate. In fact,
most of the clinical activity of isosorbide dinitrate is due to the mononitrate.
Therefore, both drugs share a similar pharmacology. Isosorbide mononitrate does not
undergo first-pass metabolism and has no active metabolites. Its oral bioavailability
is almost 100%, and its overall elimination half-life is about 5 hours.
serum concentrations are observed 30 to 60 minutes after a dose. To minimize the
potential development of nitrate tolerance, isosorbide mononitrate should be used in
a twice-daily, asymmetric dosing regimen in which the first dose is taken on
awakening and the second dose about 7 hours later. Because of this unconventional
dosing pattern and the availability of the extended-release product, which can be
General precautions and adverse reactions for isosorbide mononitrate are similar
to those for the other nitrates. Potential advantages for the clinical use of isosorbide
mononitrate are less dosage fluctuation because of the absence of presystemic
clearance and an effective once-daily or twice-daily dosing schedule, which could
perhaps lead to improved patient adherence. Nevertheless, isosorbide dinitrate is
effective clinically when administered two or three times a day and is a viable
transdermal patches a viable alternative?
Transdermal NTG patches were originally designed to provide anti-ischemic
protection with once-daily application. The concept of a compact, easy-to-apply
transdermal NTG patch prompted pharmaceutical manufacturers to design a number
of products, which the FDA subsequently approved based on plasma level data, not
clinical efficacy studies. Subsequently, the shortcomings of plasma level data have
become apparent and prompted numerous clinical efficacy studies.
Transdermal NTG therapy has been shown to increase exercise duration and
maintain an anti-ischemic effect for 12 hours after patch application. These beneficial
responses remained consistent throughout 30 days of therapy. No significant nitrate
tolerance or rebound was noted when the patch was applied for not more than 12 of
area and NTG content, the most important common denominator of the transdermal
NTG systems is the amount of drug released per hour expressed as the release rate
(e.g., 0.2 mg/hour). Each product label includes this information. Low dosages (0.2–
0.4 mg/hour) may not produce sufficient plasma and tissue concentrations to produce
a clinically significant effect
influencing NTG absorption rate, product release characteristics do not favor one
system over another. Contact dermatitis has been reported with the transdermal
patches. Patient instructions are included with the patches and should be reviewed
with the patient, emphasizing the appropriate time for application of the patch,
removal of the patch, as well as the appropriate sites on the body where the patch
prescribed sublingual NTG tablets (0.4 mg) and oral isosorbide mononitrate (60 mg once daily). B.N.
diltiazem 120 mg once daily. Is this a good option for B.N. and his chronic stable angina?
CCBs are effective in both vasospastic and classic exertional angina. These drugs
relieve vasospasm of the large coronary arteries and, as a result, are effective in
coronary circulation increase myocardial oxygen supply, whereas dilation of the
peripheral arterioles leads to a reduction in myocardial oxygen demand. Because
coronary vasospasm can occur at the site of an atherosclerotic plaque, a CCB is
particularly useful in patients who have a vasospastic component to their angina.
Although β-blockers are considered the drugs of choice when instituting
, data indicate that the selection of a heart rate–lowering CCB
may also be a reasonable first-line choice. CCBs and β-blockers appear to provide
equivalent efficacy in head-to-head trials of chronic stable angina.
patients with chronic stable angina.
In addition, several trials in the setting of
hypertension with CAD have demonstrated that CCBs can produce meaningful
It would appear that either a heart rate–lowering CCB, or
a β-blocker, may be considered relatively equal options and initial therapy for
chronic stable angina. The selection of a particular class will likely be dictated by
In the case of B.N., his asthma may be worsened by the addition of a β-blocker.
Although a cardioselective β-blocker could be tried to see if B.N. could tolerate it, a
heart rate–lowering CCB is a good alternative to a β-blocker for the treatment of
angina in this situation. The choice of a CCB as initial therapy in this patient is
appropriate due to B.N.’s previous intolerance to nitrates and because nitrate therapy
requires a nitrate-free period.
Given B.N.’s current heart rate and BP, the selection of a heart rate–lowering CCB
seems most appropriate. However, the distinct pharmacologic and adverse event
profiles of the various classes may dictate agent selection from patient to patient.
Some side effects of CCBs reflect an extension of their hemodynamic and
also may complain of light-headedness, facial flushing, headache, and nausea.
Swelling of the lower legs and ankles (peripheral edema) is related to the potent
peripheral vasodilating effects of these agents. The non-DHPs, verapamil and
diltiazem, have similar side effect profiles, although diltiazem appears to be better
tolerated. The lower incidence of side effects reported with diltiazem, compared
with verapamil, may reflect a true difference or, perhaps, less aggressive dosing
regimens. Both drugs can cause sinus bradycardia and worsen already existing
conduction defects and heart block.
40,69 Neither should be used in patients with sick
sinus syndrome or advanced degrees of heart block unless a functioning ventricular
pacemaker is present. Patients should be monitored for signs of worsening HF, such
as SOB, weight gain, and peripheral edema. Verapamil-induced constipation can be
particularly troublesome to the elderly.
Appreciation for the individual side effect profiles helps determine preference for
one CCB over another. B.N. is not likely to experience major side effects with either
CASE 12-2, QUESTION 2: On questioning, B.N. does not report any previous adverse events or tolerance
As discussed previously, the totality of available evidence supports the role of
ACE inhibitors in reducing total mortality, cardiovascular mortality, nonfatal MI, and
stroke in patients with stable IHD and preserved ventricular function. Although in
theory ARBs should produce the same beneficial effects as ACE inhibitors in
patients with atherosclerosis, there are far fewer clinical trials with ARBs. The best
supporting evidence comes from the TRANSCEND and ONTARGET trials, both of
which suggest ARBs produce similar benefits as ACE inhibitors in preventing CVD
78,79 Based on these trials, it would be reasonable to continue ARB therapy in
B.N. at this time given he has demonstrated the ability to tolerate the medication. It
would not be unreasonable though to discuss with B.N. the possibility of switching to
an ACE inhibitor given the substantial body of evidence that exists for patients with
CAD. The combination of an ACE inhibitor and ARB does not offer any increased
benefit but does increase the risk of hyperkalemia and renal insufficiency.
Calcium-Channel Blocker Hemodynamic and Electrophysiologic Profile
Heart rate Increase (reflex) Decrease or unchanged Decrease or unchanged
Nausea, vomiting + (most) +/1 ±
(Norvasc), nicardipine (Cardene), and nifedipine (Adalat, Procardia).
the basis for side effects of flushing, headache, and hypotension.
may worsen HF. Amlodipine may have the least negative inotropic effect.
Although higher doses of diltiazem might be attempted in B.N., his current heart
rate and BP would likely prevent further titrating of therapy. β-Blocker therapy is not
a good option due to the potential reduction in heart rate and asthma. Thus, ranolazine
have been conducted, all demonstrating its effectiveness at reducing ischemia and
angina when added to existing therapy. The Monotherapy Assessment of Ranolazine
in Stable Angina (MARISA) trial randomly assigned patients in a crossover fashion
who had met screening criteria to either escalating doses of ranolazine (500 mg BID,
1,000 mg BID, 1,500 mg BID) or placebo. All other antianginal agents, except for SL
NTG, were discontinued. Ranolazine significantly increased exercise duration, time
to onset of angina, and 1-mm ST-segment depression during exercise treadmill
80 Similar results were seen in the Combination Assessment of Ranolazine in
Stable Angina (CARISA) trial in which ranolazine (500 mg BID, 750 mg BID, 1,000
mg BID) was added to antianginal monotherapy that consisted of atenolol, diltiazem,
81 The Efficacy of Ranolazine in Chronic Angina (ERICA) trial
assessed the effects of ranolazine added to amlodipine 10 mg/day. Up to one-half of
the patients enrolled in ERICA were also on a long-acting nitrate. Patients were
randomly assigned to either placebo or ranolazine 500 mg/day for 1 week and then to
1,000 mg/day for an additional 6 weeks. Patients receiving 1,000 mg/day of
ranolazine had a significant reduction in both the number of weekly anginal attacks,
as well as the number of SL NTG tablets used.
82 A reduction in the frequency of
angina was also seen in patients with CAD and diabetes mellitus when ranolazine
was added in the Type 2 Diabetes Evaluation of Ranolazine in Subjects with Chronic
83 Ranolazine was well tolerated in all four of these
trials with the most common side effects being dizziness, constipation, nausea, and
headache. The incidence of adverse effects increased with increasing doses. No
other significant adverse effects were noted, although it is important to note that the
duration of these trials was limited.
Information regarding the safety of ranolazine in patients with longer drug
exposure came from the Ranolazine Open Label Experience (ROLE) program,
which followed patients from the MARISA and CARISA trials who continued in an
discontinuing therapy. One-half of the withdrawals were because of adverse
events, but the incidence of common adverse effects did not seem to change from that
seen in the randomized portions of the clinical trials. Mortality rates at both 1 year
(2.8%) and 2 years (5.6%) indicate no adverse risk of ranolazine on overall
The Metabolic Efficiency with Ranolazine for Less Ischemia in Non–ST-Elevation
Acute Coronary Syndrome (MERLIN)-TIMI 36 trial
ranolazine or placebo in the setting of ACS. Ranolazine was administered as an
intravenous (IV) infusion for 12 to 96 hours, then converted to 1,000 mg twice daily.
Patients were assessed for clinical end points during the acute hospitalization, then
every 4 months thereafter. The incidence of recurrent ischemia was significantly
reduced with ranolazine providing additional support for the efficacy of ranolazine in
treating chronic stable angina. Although ranolazine appeared to offer no benefit in the
setting of ACS, significant long-term safety data were seen in the trial. Importantly,
the risk of mortality, sudden cardiac death, or symptomatic arrhythmias was not
increased with ranolazine versus placebo. In fact, the incidence of arrhythmias in the
first 7 days, as documented by Holter monitor, was significantly lower with
86 This was an important finding given ranolazine
produces a dose-dependent increase in the QT interval.
activity has been associated with proarrhythmia in other medications, results from the
MERLIN trial are reassuring that ranolazine appears to be safe to use for chronic
treatment of patients with stable angina.
B.N. is at goal heart rate, and his BP is well controlled on his current regimen, but
he continues to have anginal symptoms. Given the demonstrated efficacy in relieving
anginal symptoms, as well as the safety profile in a patient like B.N., ranolazine
would be an excellent option for him for additional angina control.
CASE 12-2, QUESTION 4: How should ranolazine be dosed in B.N.?
Ranolazine is marketed as an extended-release tablet formulation that should be
dosed twice daily. Maximal plasma concentrations are observed 4 to 6 hours after
administration of the extended-release formulation with a terminal half-life of 7
hours. With twice-daily dosing of the extended-release preparation, a more favorable
peak-to-trough fluctuation of 1.6 is observed.
41 Steady-state is typically reached
within 3 days and oral bioavailability is 30% to 55%. Ranolazine is primarily
metabolized by the liver through CYP3A4 (70%–85%) and CYP2D6 (10%–15%).
Ranolazine also is a substrate for P-glycoprotein.
15,41 Patients should initially be
started at an oral dose of 500 mg twice daily, which can be titrated up to a maximal
Although ranolazine is an option in the treatment of chronic stable angina, careful
patient selection is required for the drug to be used safely and effectively.
12-7 summarizes significant issues, which should be evaluated when the drug is
being considered for a patient. For B.N., the main issue is the drug–drug interaction
with diltiazem, and the maximum dose of ranolazine that should be used in patients
receiving diltiazem is 500 mg twice daily. B.N. should be monitored closely for
possible increased adverse effects with ranolazine.
prevention of CAD with aspirin appropriate for E.R.’s brother?
Considerations for the Use of Ranolazine in Patients with Chronic Stable
Clinical Issue Recommended Management Strategy
Renal insufficiency Ranolazine plasma levels may increase up to 50%. Caution with dose titration
Hepatic insufficiency Ranolazine is contraindicated in patients with clinically significant hepatic
Drug Interactions: Effects on Ranolazine
with potent inhibitors of CYP3A4. Ranolazine is contraindicated in patients
receiving strong CYP3A4 inhibitors (ketoconazole, clarithromycin, nelfinavir,
Moderate CYP3A4 inhibitors Limit the dose of ranolazine to 500 mg twice daily in patients receiving
moderate inhibitors of CYP3A4 (diltiazem, verapamil, erythromycin,
CYP3A4 inducers Coadministration of ranolazine with CYP3A4 inducers is contraindicated and
Drug Interactions: Effects on Other Medications
Simvastatin Plasma levels of simvastatin are increased twofold with coadministration with
ranolazine through CYP3A4 inhibition by ranolazine; closely monitor for
adverse effects (e.g., myositis) from simvastatin
Digoxin Ranolazine coadministration increases plasma concentrations of digoxin by 1.5
times. Adjust dose of digoxin accordingly to maintain desired therapeutic level
CYP2D6 substrates Ranolazine can inhibit the activity of CYP2D6, and plasma concentrations of
2D6 substrates (β-blockers, tricyclic antidepressants, antipsychotics) may be
increased and lower doses of these agents may be required
QT prolongation Caution is recommended if the patient is on other QT prolonging drugs, or has
The question of whether aspirin is valuable in the primary prevention of
cardiovascular events has been debated for more than 20 years. The absolute risk–
benefit ratio for aspirin in primary prevention will depend on the overall absolute
risk of vascular ischemic events. Several meta-analyses suggest that any benefit for
aspirin in reducing ischemic events is offset by an increase in bleeding, resulting in
In 2009, the US Preventative Services Task Force developed updated guidelines
for aspirin use in primary prevention incorporating at the time of the most recent
91 Recommendations are differentiated initially by age and sex,
recognizing that the ischemic benefit varies between men (reduction in nonfatal MI)
and women (reduction in ischemic stroke). Aspirin for primary prevention may be
considered for men aged 45 to 79 years, and in women aged 55 to 78 years. Because
E.R.’s brother is 64 years of age, it is appropriate for him to consider the use of
aspirin for primary prevention. The first step is to calculate what his risk is for
25 This can be done by using a validated risk assessment scoring
system, such as the Framingham risk score (see Chapter 8, Dyslipidemias,
Atherosclerosis, and Coronary Heart Disease). Based on his age, if his 10-year risk
of CVD is greater than 9%, the CVD benefit with aspirin will outweigh any potential
bleeding harm according to the US Preventative Service Guidelines.
the existing controversy surrounding the use of aspirin for primary prevention, a
thorough review of the potential risk and benefits should take place with E.R.’s
brother so that he may make the most informed decision possible.
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