Download current therapeutic options and evolving therapies for chronic stable

PROCEEDINGS
CURRENT THERAPEUTIC OPTIONS AND EVOLVING THERAPIES FOR
CHRONIC STABLE ANGINA/CHRONIC CORONARY SYNDROME*
—
Prakash C. Deedwania, MD, FACC, FAHA, FCCP, FACP,† and Kanu Chatterjee, MD, FRCP, FCCP, FAHA, FACC, MACP‡
ABSTRACT
Chronic stable angina (CSA), a subset of
chronic coronary syndrome (CCS), is most often
caused by myocardial ischemia—the result of an
imbalance between myocardial oxygen demand
and supply. Many currently available therapeutic
agents for CSA will relieve the symptoms of angina but not change the ischemic threshold. The
American College of Cardiology/American
Heart Association guideline was last updated in
2003 and will again be updated later this year.
The guideline recommends aspirin, lipid-lowering
agents, beta blockers, and angiotensin-converting enzyme inhibitors as primary preventive therapy to reduce the risk of death and myocardial
infarction. Several large studies have been published to support the use of these drugs for
CSA/CCS. Percutaneous coronary intervention
(PCI) is being used more frequently as nonpharmacologic management, but some patients continue to have angina despite PCI and optimal
doses of antianginal drugs. Refractory angina is
quite common and numerous pharmacologic
*Based on presentations by Drs Deedwania and
Chatterjee at a think tank held May 13, 2006, in Deer
Valley, Utah.
†Professor of Medicine, UCSF School of Medicine, San
Francisco, California; Chief, Cardiology Section, Director,
Cardiovascular Research, VA Central California Healthcare
System/UCSF Program, Fresno, California; Clinical
Professor of Medicine, Stanford University, Palo Alto,
California.
‡Ernest Gallo Distinguished Professor of Medicine,
Director, Chatterjee Center for Cardiac Research, UCSF
School of Medicine, San Francisco, California.
Address correspondence to: Prakash Deedwania, MD,
FACC, FAHA, FCCP, FACP, VA Central California
Healthcare System/UCSF Program, 2615 East Clinton
Avenue, Fresno, CA 93703. E-mail: [email protected].
Johns Hopkins Advanced Studies in Medicine
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treatments are available. Recommended nonpharmacologic treatments include transmyocardial laser revascularization, enhanced external
counterpulsation, and spinal cord stimulation.
Additionally, there are now several new mechanistic approaches to managing coronary artery
disease, including inhibition of late sodium channels, inhibition of free fatty acid metabolism, inhibition of rho-kinase, preconditioning, and sinus
node inhibition. This article reviews some of these
new drugs, which will hopefully provide additional treatment choices. Nonetheless, the importance of comprehensive management of
myocardial ischemia, including symptom management, aggressive risk factor reduction,
antiplatelet therapy, and lifestyle modifications,
cannot be overstated.
(Adv Stud Med. 2006;6(9A):S827-S836)
T
o understand the treatments for chronic stable angina (CSA)/chronic coronary syndrome (CCS), it is important
to remember its most likely cause:
myocardial ischemia—the result of an
imbalance between myocardial oxygen demand and
supply. Oxygen supply to the heart is determined by
blood flow and oxygen extraction. Myocardial
ischemia may result from a disproportionate increase
in myocardial oxygen demand or inappropriate
decrease in coronary blood flow, and rarely reduced
oxygen-carrying capacity of the blood. Therefore, any
increase in myocardial oxygen demand (eg, during
exercise) must be offset by a proportional increase in
coronary blood flow. The direct, linear relationship
between oxygen consumption and blood flow is well
established in animals and humans.1 When there is a
mismatch between myocardial oxygen demand and
coronary blood flow, ischemia will result (ie, the
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PROCEEDINGS
ischemic threshold; Figure 1). Coronary stenosis or
decrease in coronary flow reserve will decrease the
ischemic threshold (Figure 1). As will be discussed
later in this article, many therapeutic agents for
CSA/CCS will relieve the symptoms of angina but will
not change the ischemic threshold.
Sidebar. Mnemonic for Treatment of Chronic
Coronary Syndrome
A = Aspirin and antianginal therapy
B = Beta-blocker and blood pressure
C = Cigarette smoking cessation and cholesterol
PHARMACOTHERAPY FOR CCS
D = Diet and diabetes
E = Education and exercise
PHARMACOTHERAPY TO PREVENT MI OR DEATH
Data from Gibbons et al.2
Figure 1. Ischemia Threshold in Stable Angina
Normal
Coronary blood flow
The goals of pharmacotherapy for CCS are 2-fold:
to reduce the risk of myocardial infarction (MI) and
death, which is presumably accomplished by several
mechanisms, including reducing or stabilizing the atherosclerotic plaque and reducing the likelihood of
plaque rupture and acute coronary syndrome; and to
improve anginal symptoms and reduce myocardial
ischemia by optimizing the myocardial oxygen supply-demand balance. Note that the goals are to
increase quantity and quality of life. Recommended
treatments for decreasing the risks of infarction and
death include aggressive statin therapy, beta blockers, aspirin, angiotensin-converting enzyme (ACE)
inhibitors, and lifestyle modifications. Drugs that
improve anginal symptoms include drugs that
reduce heart rate, blood pressure, contractility, and
venous return to the heart (ie, beta blockers, calcium blockers, and nitrates), and there are newer
agents with mechanisms of action that are different
from the established antianginal drugs. The
American College of Cardiology/American Heart
Association (AHA) guideline recommends that
treatment should include all of the elements in the
A-B-C-D-E mnemonic (Sidebar).2 This article
reviews some of the recommended treatments and
discusses future directions in CCS treatment; some
of the more common obstacles to the successful use
of established therapies are summarized in Table 1.
Ischemia threshold
S828
Decreased
flow
reserve
Ischemia threshold
Myocardial oxygen demand
Table 1. Treatment Challenges for Coronary Artery
Disease
Treatment
The guideline now recommends aspirin, lipidlowering agents, beta blockers, and ACE inhibitors as
primary preventive therapy.2 Several large clinical trials have provided evidence to support some of these
drug classes. For example, several studies have shown
cardioprotective effects of ACE inhibitors, including
a significant reduction in MI, stroke, and death risk
in patients at increased risk for cardiovascular disease.3-6 Since the guideline was last updated, 2 other
Coronary stenosis
Challenge
Older antianginal drugs
Many patients cannot tolerate
combinations at maximal doses
Disease-modifying agents
BP, lipid, and glucose goals are being
revised downward
PCI
Many patients are not suitable candidates
Lifestyle modification
Noncompliance limits long-term benefit
BP = blood pressure; PCI = percutaneous coronary intervention.
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PROCEEDINGS
clinical trials of ACE inhibitors for CCS have been
published. The EUROPA study showed a 20% relative risk reduction (95% confidence interval [CI],
9–29; P = .0003) for cardiovascular death, MI, or
cardiac arrest with perindopril in a low-risk population with stable coronary heart disease and no apparent heart failure.7 However, the PEACE study did
not show additional benefit with ACE inhibition in
patients with stable coronary artery disease (CAD)
and preserved left ventricular function.8 Several reasons for this unexpected result have been put forth,
including the lower cardiovascular baseline risk of
the PEACE study population, which was more
intensively treated with lipid-lowering drugs and had
a greater number of patients with myocardial revascularization prior to enrollment than patients in
HOPE or EUROPA; differences in clinical efficacy
for cardiovascular endpoints between the ACE
inhibitors in each study (trandolapril in PEACE,
ramipril in HOPE, and perindopril in EUROPA);
inability to reach the projected sample size in the
PEACE study; and a “soft” endpoint of revascularization.9 Nonetheless, ACE inhibitors remain a
strongly recommended treatment.
Lipid-lowering agents (ie, statins) are now recognized not only as treatments to prevent MI or
death, but also as part of risk factor modification.2
The benefits of lowering low-density lipoprotein cholesterol for reducing coronary heart disease (CHD)
events (as both primary and secondary prevention) are
well established.10-15 Since the guideline was published
and updated, several other trials have also now shown
that statin therapy may decrease the incidence of angina and death and may decrease the frequency of angina
and ischemia during exercise tolerance testing.16,17
Specifically, the ASCOT-LLA arm showed that treatment with atorvastatin in hypertensive patients significantly lowered the incidence of fatal and nonfatal
stroke (89 atorvastatin vs 121 placebo; 0.73
[0.56–0.96]; P = .024), total cardiovascular events (389
vs 486; 0.79 [0.69–0.90]; P = .0005), and total coronary events (178 vs 247; 0.71 [0.59–0.86]; P = .0005).
The effect was so significant that the study was stopped
early.16 Another large study comparing 10-mg and 80mg atorvastatin in 10 001 patients with clinically evident CHD showed that more aggressive statin
treatment was able to offer a 22% relative risk reduction (hazard ratio, 0.78; 95% CI, 0.69–0.89; P <.001)
in primary endpoint (occurrence of a first major car-
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Table 2. Mechanisms of Action of CAD Treatments
Drug Class
Proposed Mechanism of Action
Beta-adrenergic
antagonists
• Reduction of myocardial oxygen demand by
reducing the heart rate, blood pressure, and
contractility
• May enhance myocardial perfusion due to
increase of perfusion time resulting from
bradycardia
• Increases exercise duration, but does not change
ischemia threshold
Nitroglycerin and
nitrates
• Decrease in myocardial oxygen demand by
reduction of ventricular volume and blood pressure
• Epicardial coronary artery dilatation; may be
useful in vasospastic and mixed angina
Calcium channel
blockers
• Reduction of myocardial oxygen demand by
decreasing blood pressure and contractility and with
heart rate regulating agents also by decreasing heart
rate
• Dilatation of the coronary conductance and
resistance vessels; may be useful in vasospastic
and mixed angina
• Improves exercise tolerance, usually does not
change ischemia threshold
diovascular event, defined as death from CHD, nonfatal nonprocedure-related MI, resuscitation after cardiac
arrest, or fatal or nonfatal stroke), but no additional
benefit for overall mortality.18
The only drugs that have shown benefit with
reducing symptoms are beta blockers, calcium channel
antagonists, and nitrates.2 Their proposed mechanisms
of action are outlined in Table 2. Since the guideline
was updated, a large randomized, placebo-controlled
study evaluated nifedipine gastrointestinal therapeutic
system in 7665 patients with stable symptomatic coronary disease. The primary endpoint was the combination of death, acute MI, refractory angina, new overt
heart failure, debilitating stroke, and peripheral revascularization, with mean follow-up of nearly 5 years.
Although nifedipine had no effect on major cardiovascular event-free survival, it reduced the need for coronary angiography and interventions (rate of death and
any cardiovascular event or procedure: 9.32 vs 10.50
per 100 patient-years; P = .0012).19
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PROCEEDINGS
The guideline states that therapy should be staged,
beginning with symptom management using beta
blockers. If symptoms persist, a long-acting nitrate or
calcium channel antagonist can be added, depending
on the patient’s clinical characteristics. If symptoms
continue, triple therapy may be necessary, provided
there are no contraindications.2
NONPHARMACOLOGIC TREATMENTS FOR CCS/CSA
optimal medical therapy, lifestyle modification treatments, and revascularization therapies.”23,24 It is quite
common, with more than 100 000 patients diagnosed
per year (and prevalence estimates of approximately 300
000–900 000 in the United States). Although its prognosis remains uncertain, the 1-year rate of MI and death
has been reported to be 26% to 17%, respectively.25
The updated guideline provides recommendations
for patients with refractory angina who are not candidates for PCI or revascularization. Indeed, some
patients experience incomplete angina relief post-PCI.
A study of 1632 consecutive patients who underwent
PCI showed that, at 1-year follow-up, 26% reported
experiencing angina within the previous 6 weeks,
despite relatively extensive use of adjunctive antianginal therapy—78.6% were using at least 1 antianginal
drug (27.9% were using nitrates, 29.9% calcium channel blockers, and 60.9% beta blockers).26
The potential pharmacologic treatments for refractory angina are numerous: metabolic modulators,
bradycardic agents, K+-channel activators, metformin,
thiazolidinediones, preconditioning agents, vasopepti-
72
Patients, %
Limitations of older anginal therapies and technical
improvements in intervention procedures have led to
increasing use of elective percutaneous coronary intervention (PCI) to treat stable CAD. Lucas et al found a
115% increase in PCI from 1993 to 2001, based on an
annual cross-sectional population-based study of
Medicare patients.20 By comparison, in this analysis,
coronary artery bypass grafting increased only 19% and
cardiac catheterization increased 69%.20 However,
Katritsis and Ioannidis conducted a meta-analysis of 11
randomized trials (n = 2950) that compared PCI with
conservative medical management in patients with
chronic stable CAD.21 They found that
although PCI effectively relieves angina, it
does not offer any long-term advantage over
medical management in terms of death, MI,
or need for additional revascularization.21
Figure 2. Major Benefit of PCI is Angina Symptom Relief
Similarly, Spertus et al showed that patients
with stable CAD and angina are more likely
to have improved quality of life following PCI
80
Angina absent
Angina present
than those who have CAD but are free from
70
angina.22 In this study, the majority of
60
51
patients with angina (72%) reported a large
50
improvement in quality of life following elec40
tive PCI compared to only 19% of patients
30
19
who were symptom-free (Figure 2).22 Thus,
17
20
13
12
the major benefit of PCI in stable CAD is
10
angina relief.
0
No change
TREATMENT FOR REFRACTORY ANGINA
Within the spectrum of CCS lies refractory angina, defined as “Canadian
Cardiovascular Society (CCS) class III or IV
angina (ie, marked limitation of ordinary
physical activity or inability to perform ordinary physical activity without discomfort)
with objective evidence of myocardial
ischemia and persistence of symptoms despite
S830
Moderate improvement
Large improvement
Change in SAQ score
A total of 1518 patients were prospectively followed. Of these, 1102 patients underwent elective PCI, survived, and were followed up 1 year later to measure quality of life using the SAQ.
The strongest predictors of quality-of-life improvement 1 year after PCI were baseline angina frequency and physical function.
Change in SAQ Score:
No change: -10 to 10 points.
Moderate improvement: 10 to 20 points.
Large improvement: >20 points.
PCI = percutaneous coronary intervention; SAQ = Seattle Angina Questionnaire.
Adapted with permission from Spertus et al. Circulation. 2004;110:3789-3794.22
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PROCEEDINGS
dase inhibitors, nitric oxide (NO)-donors, capFigure 3. Sites of Action of Anti-Ischemia Medication
saicin, diuretics, gene therapy, and autologous
bone marrow, in addition to rho-kinase inhibitors
and ranolazine (both discussed later in this artiDevelopment of Ischemia
Consequences of Ischemia
cle). There are also numerous options for nonpharmacologic treatment of refractory angina:
O2 Demand
• Electrical instability
transmyocardial laser revascularization (TMLR),
• Heart rate
• Myocardial dysfunction
Ischemia
enhanced external counterpulsation (EECP),
• Blood pressure
( systolic function/
(Na+ / Ca++ overload)
• Preload
spinal cord stimulation (SCS), percutaneous
diastolic stiffness)
• Contractility
myocardial revascularization, transcutaneous
O2 Supply
Ranolazine
electrical nerve stimulation, programmed exerConventional
anti-ischemic
cise, extracorporeal cardiac shock wave therapy,
Compression
medications
temporary sympathectomy, and cardiac transof nutritive
blood vessels
• β blockers
plantation. The updated guideline states Class
• Nitrates
IIa recommendations for TMLR, and Class IIb
• Ca++ blockers
recommendations for EECP and SCS. TMLR is
based on the premise that open transmyocardial
channels will lead to angiogenesis. TMLR studies to date have all been open trials (ie, no shamthe spinothalamic tract. Similar to EECP, the mechacontrolled studies). Although TMLR has shown no
nism is not completely understood, but it may decrease
effect on mortality, it may improve anginal symptoms
ischemia and improve myocardial blood flow by
and exercise tolerance.27
decreasing sympathetic tone.
Enhanced external counterpulsation has been
shown to improve several measures of CAD symptoms,
NEW MECHANISTIC APPROACHES TO
including angina, nitrate use, exercise tolerance, time to
MANAGEMENT OF CAD
exercise-induced ST-segment depression, and myocardial perfusion.28-36 EECP is conducted as 35 1-hour sesThere are now several new mechanistic approaches
sions, 1 to 2 times per day. It acts by inflating/deflating
to managing CAD, including inhibition of late sodicuffs, which serve to increase diastolic aortic pressure
um channels, inhibition of free fatty acid metabolism,
(with subsequent increase in coronary perfusion presinhibition of rho-kinase, preconditioning, and sinus
sure) and reduce systolic pressure (thereby attenuating
node inhibition.
the cardiac workload and promoting venous return,
Ranolazine has been studied in 4 large clinical trials.
which increases cardiac output).37 However, the exact
It is thought to modify the pathophysiology of CAD
mechanisms for the beneficial effects remain unclear.
through several potential mechanisms: inhibition of late
Bonetti et al evaluated the efficacy of EECP and its proinward Na+ current, which is increased during ischemia
posed mechanism using reactive hyperemia-peripheral
and CHF; decreasing Na+ overload; decreasing Ca2+
arterial tonometry (RH-PAT), a noninvasive method to
overload; decreasing metabolic dysfunction; decreasing
assess peripheral endothelial function.37 RH-PAT meaischemia-induced diastolic and systolic mechanical dyssures reactive hyperemic response in the finger. Based
function; and decreasing ischemia-induced electrical dyson their study results, the investigators propose that the
function. Although conventional anti-ischemic
delayed improvement in parameters of endothelial
medications act by preventing development of ischemia
function with EECP may be due to the increased activ(Figure 3), ranolazine is thought to act by preventing the
ity and expression of endothelial NO synthase from
consequences of ischemia, namely electrical instability
increased shear stress, which is generated by a standard
and myocardial dysfunction. Importantly, the mechacourse of EECP.37
nisms for decreasing myocardial ischemia and angina by
Spinal cord stimulation consists of 3 1-hour stimuranolazine are not due to a decrease in myocardial oxylations per day. An epidural lead is placed at the level of
gen demand nor a primary increase in coronary blood
C7-T1 in a subcutaneous generator. The applied elecflow (Table 3).2,38,39 The first study of ranolazine was the
tric impulse inhibits transmission of nerve impulses via
Monotherapy Assessment of Ranolazine in Stable
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PROCEEDINGS
S832
Table 3. Pathophysiologic Effects of Ranolazine Versus Older
Antianginal Drugs
O2 Supply
O2 Demand
Coronary
blood flow
Heart
rate
Arterial
pressure
Venous
return
Myocardial
contractility
—
↓
↓
—
↓
DHP CCB
↑
↑*
↓
—
↓
Non-DHP CCB
↑
↓
↓
—
↓
Long-acting nitrates
↑
↑/—
↓
↓
—
—
—
—
—
—
Class
β-blockers
Na+
Late
current
inhibitors
(ranolazine)
†
*Except amlodipine.
†Ranolazine: no direct effect but may prevent ischemia-related decline.
CCB = calcium channel blocker; DHP = 1,4 dihydropyridine.
Data from Gibbons et al2; Boden et al38; Kerins et al.39
Figure 4. Ranolazine Improves Exercise Capacity in Combination
with Standard Antianginal Therapies:The CARISA Study
Trough
Peak
*
150
Change from baseline, sec
Angina trial, which was a randomized, doubleblind, placebo-controlled, crossover study in 191
patients with angina-limited exercise. Patients were
randomized to receive sustained-release ranolazine
500, 1000, or 1500 mg, or placebo, each administered twice daily for 1 week. The results showed
significant improvements in exercise duration,
time to angina, and time to 1-mm ST-segment
depression. One-year survival was 96.3% ±
1.7%—an expected rate for this high-risk population.40 Similarly, ranolazine (400 mg immediate
release, 3 times daily) was compared to atenolol
(100 mg/day) or placebo in 158 patients with
symptom-limited exercise in a double-blind, 3period, crossover study. Exercise tests were administered at the end of each treatment period.
Ranolazine was shown to be at least as effective as
atenolol in increasing exercise duration, time to 1mm ST-segment depression, and time to onset of
angina. Ranolazine achieved these endpoints without decreasing blood pressure, heart rate, or ratepressure product to a clinically significant degree.41
Ranolazine was also evaluated in combination
with atenolol or diltiazem in 823 patients with
angina/ischemia, despite standard daily doses of
these traditional drugs. The results showed significant improvements in exercise duration, time to
angina, and time to 1-mm ST-segment depression,
in addition to reduced nitrate use and number of
weekly anginal episodes (Figure 4), without
adverse long-term survival consequences over 1 to
2 years of treatment.42 Ranolazine (1000 mg sustained-release, twice daily) has been evaluated as
combination therapy in patients with chronic
angina taking amlodipine 10 mg. Early analysis
shows significant improvement in patients treated
with ranolazine compared to placebo regarding
number of angina episodes and nitroglycerin consumption per week, with consistent treatment
effect across subgroups (ie, long-acting nitrate users
vs non–long-acting nitrate users; men vs women;
patients aged <64 years vs patients ≥65 years).43
Trimetazidine inhibits one of the enzymes
involved in fatty acid oxidation, which results in
increased myocardial glucose oxidation. During
ischemia, myocytes shift from glucose oxidation
to fatty acid oxidation, creating ionic species
within the cell. Trimetazidine is thought to protect the myocyte from these ionic and metabolic
*
†
*
†
*
‡
‡
‡
†
*
100
50
Exercise
duration
Time
to angina
Time to 1-mm
ST depression
Placebo
Exercise
duration
750 mg BID
Time
to angina
Time to 1-mm
ST depression
1000 mg BID
CARISA was a randomized, 3-group parallel, double-blind, placebo-controlled trial of 823 eligible adults with symptomatic chronic angina. Participants were randomly assigned to receive
placebo or ranolazine 750 mg twice daily or 1000 mg twice daily. Patients were already taking
atenolol 50 mg every day, diltiazem 180 mg every day, or amlodipine 5 mg every day. The
main outcome measures were: change in exercise duration, time to onset of angina, time to
onset of ischemia, nitroglycerin use, and number of angina attacks. Survival of the ranolazinetreated patients during the CARISA study or its associated long-term open-label study was
98.4% in the first year and 95.9% in the second year. Ranolazine also significantly reduced angina attacks and nitroglycerin use by approximately 1 per week compared to placebo (P <.02).
n = 791.
*P <.05.
†P ≤.01.
‡P ≤.001 vs placebo.
BID = twice daily; CARISA = Combination Assessment of Ranolazine in Stable Angina.
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changes. With established efficacy as monotherapy or
in combination with beta blockers or calcium channel
antagonists, the Trimetazidine in Poland study was
designed to assess the efficacy and tolerability of
trimetazidine in combination with metoprolol in
patients with stable effort angina.44 The results showed
significant improvement with trimetazidine compared
to placebo in time to 1-mm ST-segment depression,
total workload, time to onset of angina, maximum STsegment depression, mean weekly number of angina
attacks, mean weekly nitrate consumption, and grade
of anginal pain—with no evidence of developing tolerance to trimetazidine.44 It is now widely used in Europe
and India for angina.
A rho-kinase inhibitor is also being evaluated for stable angina. Rho-kinase is an intracellular signaling molecule involved in the vascular smooth muscle contractile
response to agonists (eg, acetylcholine, angiotensin II,
and norepinephrine). Rho-kinase phosphorylates and
inactivates myosin regulatory light chain phosphatase,
resulting in sustained contraction. Therefore, rho-kinase
inhibition results in systemic and coronary vasodilation.
A phase II, randomized, placebo-controlled clinical trial
of fasudil, a rho-kinase inhibitor, in 84 patients with stable angina has recently been completed.45 The results
showed that fasudil 80 mg (up to 3 times daily) significantly increased ischemic threshold and improved
Seattle Angina Questionnaire scores. However, no significant differences were noted in CCS class, time to
angina, or frequency of angina or nitroglycerin use
between the 2 treatment groups. Because there was no
change in rest or exercise heart rate and blood pressure,
the effect of fasudil may be related to increase in blood
flow rather than changes in oxygen demand.45 Clearly,
further studies are needed.
Ivabradine is a sino-atrial node inhibitor. It is a
selective, heart-rate lowering drug that inhibits the
hyperpolarization-activated, mixed sodium/potassium
inward If current, which is a primary SAN pacemaker
current. Ivabradine is thought to work in stable angina by improving myocardial perfusion and reducing
myocardial oxygen demand from the lowered heart
rate. In a double-blind, placebo-controlled, randomized trial of 360 patients with chronic angina, ivabradine (2.5 mg, 5 mg, and 10 mg twice daily) or placebo
was administered for 2 weeks, followed by an openlabel 2- or 3-month extension on ivabradine (10 mg
twice daily) and a 1-week randomized withdrawal to
ivabradine (10 mg twice daily) or placebo. The study
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showed dose-dependent improvements in exercise tolerance and time to development of ischemia during
exercise with ivabradine. Specifically, in the per-protocol population (n = 257), significant improvements in
time to 1-mm ST-segment depression were observed
in the 5- and 10-mg twice-daily groups (P <.005), in
addition to time to limiting angina in the 10-mg
twice-daily group (P <.05). Also, all exercise tolerance
test parameters deteriorated in patients who received
placebo during randomized withdrawal (all P <.02),
but not in those still receiving ivabradine.46
Several other treatments are also under investigation
for refractory angina. For example, gene therapy and use
of recombinant proteins are used to deliver angiogenic
cytokines (vascular endothelial growth factor, bFGF,
aFGF, and FGF-4) to induce therapeutic myocardial
angiogenesis.47-54 One study compared heparin to
adenosine.55 Granulocyte macrophage colony-stimulating factor is being used to mobilize bone marrow stem
cells to induce angiogenesis, with some initial promising
results.56,57 Cell implantation therapy involves the direct
intramyocardial percutaneous delivery of autologous
bone marrow in patients with myocardial ischemia to
induce angiogenesis. A feasibility study in 10 patients
was successful with no periprocedural complications
and no major cardiac events after 1 year of follow-up.
Severity of angina in some patients and quality of life
improved in all study patients. Myocardial perfusion of
the target areas improved in 4 of 8 patients.58 Similarly,
another study followed 15 patients with chronic refractory angina for 1 year who underwent transcoronary
sinus administration of autologous bone marrow. No
deaths or MI were observed during the follow-up. Mean
angina measures improved significantly and perfusion
imaging showed improvement in 12 of 15 patients,
whereas coronary angiography showed more collateral
vessels in 66% of the study patients.59
FUTURE DIRECTIONS IN ANTIANGINAL THERAPY
Despite various medical therapies and/or revascularization, some patients continue to experience angina. For these patients, management of their CCS in
the primary care setting (where many patients are
managed) appears to be suboptimal. In a cross-sectional analysis of more than 7000 veterans with selfreported coronary heart disease, 30% of the study
participants experienced angina or took sublingual
nitroglycerin more than twice a week. Of these
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patients with frequent angina, 22% were not taking
any antianginal medications, 33% were only taking 1
antianginal drug, and 50% of those taking antianginal
drugs were not taking the recommended doses.60 Thus,
while our current treatment options for recurrent angina are limited and/or are not being used at the recommended dosages, consensus on the role of newer
treatments is pending. Thus, how do we best manage
symptomatic patients?
Treatments for angina have evolved from focusing
strictly on symptom relief to more disease-modifying
approaches, and both have shown benefit in patients
with CAD. We are now seeing data indicating that the
effects of drug therapy (for symptom relief ) and
lifestyle changes are independent and additive.
In a study of 409 patients with CAD, Sdringola et al
measured quantitatively the size and severity of perfusion defects by dipyridamole positron emission tomography at baseline and after 2.6 years of follow-up, with
additional follow-up at 5 years.61 Patients received one
of the following treatment regimens: “poor” treatment
(no drugs or diet changes), “moderate” treatment (AHA
diet and lipid-lowering drugs or strict low-fat diet), or
“maximal” treatment (strict low-fat diet, exercise, and
lipid-lowering drugs with specific lipid targets). The
results showed “dose-dependent” effects on coronary
events (5-year follow-up) and perfusion abnormalities
(2.6-year follow-up). The percentage of patients experiencing coronary events after 5 years were 6.6%, 20.3%,
and 30.6% in patients treated with maximal, moderate,
and poor treatment regimens, respectively. Similarly, the
size and severity of perfusion abnormalities increased for
those receiving moderate and poor treatments, but
decreased for those receiving maximal treatments (P =
.0001 and P = .003, respectively).61 Although the study
population was not randomized, the data strongly support a multidimensional approach to treating CAD,
including pharmacologic treatments and lifestyle
changes, as primary and secondary prevention.
Very recently, data have shown that more aggressive
medical management provides advantages over less
aggressive management, as demonstrated by less disease
progression and fewer clinical events. The Clinical
Outcomes Utilizing Revascularization and Aggressive
Drug Evaluation trial tests whether PCI plus aggressive
medical therapy (ie, lifestyle modification and
antiplatelet, antianginal, blood pressure- and glucoselowering, and lipid-modifying therapies) is superior to
PCI alone. More than 2200 patients were randomized
S834
and will be followed for 5 years to compare the outcomes.62 Similarly, the Bypass Angioplasty
Revascularization Investigation 2 Diabetes study uses a
2 x 2 factorial design to compare the effects of revascularization plus medical therapy versus medical therapy
alone and insulin sensitizer-based diabetes treatment
versus insulin-based treatment (with both achieving a
similar goal of glycemic control). More than 2300
patients have been randomized and will be followed for
5 years. The study was undertaken because patients with
diabetes respond less favorably to PCI and surgery compared to patients without diabetes.63
CONCLUSIONS
The goals of antianginal therapy in CCS are to
reduce myocardial oxygen supply-demand balance to
improve ischemia/anginal symptoms and to provide
secondary prevention therapy. Current therapies,
although effective in many patients, insufficiently control symptoms/ischemia in others. New agents will
hopefully provide additional choices due to mechanisms of action not previously available, but the
importance of comprehensive management of MI,
including symptom management, aggressive risk factor reduction, antiplatelet therapy, and lifestyle modifications, cannot be overstated.
View Highlights from the group discussion
that followed this presentation:
www.jhasim.com/ccs
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