Download Clinical and research issues regarding chronic advanced coronary

Results of Expert Meetings
Clinical and research issues regarding chronic
advanced coronary artery disease:
Part I: Contemporary and emerging therapies
E. Marc Jolicoeur, MD, MSc, a Christopher B. Granger, MD, a Timothy D. Henry, MD, b David J. Holmes, MD, c
Carl J. Pepine, MD, d Daniel Mark, MD, a Bernard R. Chaitman, MD, e Bernard J. Gersh, MB, ChB, DPhil, f
and E. Magnus Ohman, MD a on behalf of the Working Group Members g Durham, NC; Rochester, MN;
Gainesville, FL; and St. Louis, MO
The following report is based on a working group meeting about advanced coronary artery disease for patients with refractory
ischemia who cannot receive revascularization. The aims were to review currently available treatment strategies, define
unmet clinical needs, explore clinical trial design issues, and identify promising novel therapeutic targets and approaches for
patients with chronic ischemia. The Working Group brought together medical experts in the management of refractory
angina with representatives from regulatory agencies, Centers for Medicare and Medicaid Services, and industry. The meeting
began with presentations reviewing the limitations of the current medical therapies and revascularization strategies and focused
on lessons learned from past therapeutic attempts to optimize outcomes and on what are considered to be the most promising new
approaches. Perspectives from clinical experts and from regulatory agencies were juxtaposed against needs and concerns of
industry regarding development of new therapeutic strategies. This report presents the considerations and conclusions of the
meeting on December 4-5, 2006. This document has been developed as a 2-part article, with contemporary and emerging
therapies for advanced coronary artery disease reviewed first. Trial design, end points, and regulatory
issues will be discussed in the second part of the article. (Am Heart J 2008;155:418-34.)
Part I. Contemporary and emerging
therapies
The population of patients with advanced coronary
artery disease (CAD) is growing as a result of the aging
of the general population, more extensive use of
revascularization, and more effective therapies that
have prolonged the survival of patients with severe
atherosclerosis. Patients with refractory angina who
have exhausted most therapeutic options comprise a
growing clinical entity and a therapeutic dilemma.
Nonetheless, advanced CAD receives relatively little
attention from the medical and research communities.
As a result, the scope of the disease is not well defined,
From the aDuke University, Durham, NC, bMinneapolis Heart Institute Foundation, MN,
c
Mayo Clinic, Rochester, MN, dUniversity of Florida, Gainesville, FL, eSaint Louis University
School of Medicine, St. Louis, MO, and fMayo Clinic and Foundation, Rochester, MN.
g
See Appendix A for complete group membership.
Dr. E. Marc Jolicoeur is supported by the Montreal Heart Institute Foundation and by the
Quebec Cardiologists Association.
Submitted November 30, 2007; accepted December 6, 2007.
Reprint requests: E. Marc Jolicoeur, Box 3850, 2400 Pratt Street Room 0311, Terrace
Level, Durham, NC 27705.
E-mail: [email protected]
0002-8703/$ - see front matter
© 2008, Mosby, Inc. All rights reserved.
doi:10.1016/j.ahj.2007.12.004
its coverage in guidelines from professional associations
is scant,1,2 and few new medical options are available.3
This report reviews the current status of advanced
CAD, the limits of the contemporary available therapies,
and the difficulties encountered in the development of
new approaches.
Definition of advanced CAD
Advanced CAD has been recognized under several
terms and classifications: intractable angina pectoris, nooption CAD, nonrevascularizable CAD, and end-stage
CAD. Truly, refractory angina embodies several chronic
coronary artery syndromes that vary in their manifestation and pathophysiology. The syndromes of chronic
CAD, their definitions, and suggested pathophysiology
are summarized in Table I.
Recently, a European Society of Cardiology Joint
Study Group on the Treatment of Refractory Angina
proposed the following definition: “A chronic condition (N3 months) characterized by the presence of
angina caused by coronary insufficiency in the
presence of CAD, which cannot be controlled by a
combination of medical therapy, angioplasty, and
coronary bypass surgery. The presence of reversible
myocardial ischemia should be clinically established to
be the cause of the symptoms.” 4 Advanced CAD could
American Heart Journal
Volume 155, Number 3
Jolicoeur et al 419
Table I. Clinical syndromes of chronic CAD
Syndromes
Clinical definition
Suggested pathophysiology
CSA
Deep chest/arm discomfort,
↑ with exercise/psychological stress,
↓ by rest/nitroglycerin
Increase in myocardial oxygen demand with
epicardial flow limitation
Isolated angina
Symptoms similar to CSA with no prior
MI or revascularization
Same as CSA
Revascularization-resistant angina
Symptoms similar to CSA but successful
prior revascularization
Combination of epicardial endothelial
dysfunction, microvascular angina,
and sensitive heart syndrome
Refractory angina
Symptoms similar to CSA but unsuccessful
prior revascularization
Increase in myocardial oxygen demand
with marked epicardial flow limitation
Persistent angina
Symptoms similar to CSA with recurrence
on medical therapy
Same as CSA with pharmacologic
resistance and microvascular angina
Microvascular angina (syndrome X)
Symptoms may or may not be similar
to CSA with evidence for myocardial;
ischemia and “normal” coronary angiogram
(no flow-limiting stenosis)
Altered cardiac nociception, endothelial
dysfunction, impaired microvascular
dilation ± vascular smooth muscle dysfunction
Variant angina (Prinzmetal)
Symptoms similar to CSA, usually at rest and
early am hours, episodic coronary spasm
with ST-segment elevation
VSMC hypersensitivity to vasoconstrictor stimuli +
↓ endothelium-derived relaxing factors.
May involve microvascular spasm
Silent ischemia
Asymptomatic episodes in patients with
obstructive CAD with or without CSA
Defective nociception through narcotics,
neuropathy or advanced age
Sensitive heart syndrome
Lack of evidence of ischemia with
cardiac related pain
Decreased threshold for nociception ±
sympathovagal imbalance
CSA, Chronic stable angina; VSMC, vascular smooth muscle cells.
be more practically defined as symptomatic multivessel
CAD in patients who are not candidates for revascularization with either percutaneous coronary
intervention (PCI) or coronary artery bypass grafting
(CABG) surgery.
The reasons why a patient may not be revascularizable
include unsuitable coronary anatomy, surgery-related
issues (previous CABG, lack of surgical conduits, multiple
thoracotomies, extensive aortic calcification), extracardiac comorbid illnesses (renal failure, chronic obstructive
pulmonary disease), and advanced age (which often
combines the above-mentioned features). However, the
“nonrevascularization” status also will be influenced by
local expertise, operator tolerance to risk, and patient
agreeing to the procedure. Likewise, the threshold for
revascularization may be modified depending on the
clinical context.
Prevalence of advanced CAD
Precise estimates of the prevalence of advanced
CAD in a global population are not available.
However, rough estimates have been obtained from
population surveys and catheterization laboratory
registries. In the late 1990s, Mukherjee et al5 reported
that 12% of the patients referred for symptomatic
CAD were not amenable to PCI or CABG.
In absolute numbers, this would represent more than
100 000 patients per year in the United States. This
proportion is somewhat similar to Swedish surveys in
which 10% of the patients did not undergo revascularization despite severe angina symptoms.6,7 Inferences from catheterization laboratory registries should
be interpreted with caution, however, because
referrals for angiography are generally biased by
patients initially deemed by their physicians to be
candidates for revascularization. This referral bias
likely leads to an underestimate of the true prevalence of chronic refractory angina because the most
morbid patients are probably not included in the
denominator. Using the same logic, this referral bias
may lead to an overrepresentation of unsuitable
anatomy (or lack of graft material) as a reason for
revascularization ineligibility.
Mortality associated with advanced CAD
In patients with chronic stable angina, the annual
mortality rate is approximately 1.5%.8 For advanced
CAD, few mortality and morbidity data have been
American Heart Journal
March 2008
420 Jolicoeur et al
Table II. Mortality and adverse cardiac events associated with optimal medical therapy in refractory angina trials
Study therapy,
year
Design (n)
Relevant inclusion/
exclusion criteria
Mortality and
morbidity in
control group ⁎
Comments
Schofield et al15 TMR, 1999
RCT (188)
Control: medical
E: LVEF N30%,
unable to do treadmill,
life expectancy b12 mo
Death: 4% at 12 mo
ACS: 63% at 12 mo
Medical therapy not
detailed ACS expressed as
0.8 per patient-year (n = 83)
ATLANTIC11 TMR, 1999
RCT (182)
Death: 10% at 12 mo
Control: medical
I: At least one protected
vascular territory
E: LVEF b30%, unable
to do treadmill
Protected region defined as
unobstructed blood flow
(lesion b50%) or patent CABG:
65% had a protected LAD
Frazier et al12 TMR, 1999
RCT (192)
Control: medical
E: LVEF b20%,
concurrent major illness
Death: 21%
ACS: 69% at 12 mo
18 patients underwent
revascularization procedure
despite being
nonrevascularizable initially.
At 5 y; the number
goes up to 35
Allen et al10 TMR, 1999
RCT (275)
Control: medical
I: Class IV angina only
E: LVEF b25%, severe COPD
Death: 11% at 12 mo
ACS: 69% at 12 mo
The incapacity to
undergo a stress test was
not an inclusion criterion.
PACIFIC14 TMR, 2000
RCT (221)
Death: 3% at 12 mo
ACS: 53% at 12 mo
CHF: 10% at 12 mo
Control: medical
E: LVEF b30%, unable to do
treadmill, symptomatic heart
failure, renal insufficiency,
moderate AS, severe PAD
24 patients had PTCA/CABG
or TMR during follow-up.
Nonrevascularization
assessment poorly defined
Aaberge et al9 TMR, 2000
RCT (100)
Control: medical
E: age N75 y, LVEF b30%,
overt heart failure
Death: 8% at 12 mo
ACS: 40% at 12 mo
Medical therapy is optimal
with rate of administration
higher than 80%
Leon at al 13 TMR, 2005
RCT (298)
E: unable to do treadmill,
chronic AF
Death: 5% at 12 mo
ACS: 3% at 12 mo
MACE: 11% at 12 mo
Medical therapy group
underwent sham invasive
procedure (may affect survival)
E: LVEF b30%,
unstable cardiac condition or
revascularization within the
past 3 mo, renal dysfunction
Death: 1% at 6 mo
ACS: 15% at 6 mo
MACE: at 6 mo
Placebo patients underwent
intracoronary placebo injection
with no complication.
Hypotension associated
with dosing was reported
Control: placebo
FIRST19 rFGF-2, 2002
RCT (337)
Control: placebo
ACS: 77% at 12 mo
CHF: 10% at 12 mo
VIVA16 rhVEGF, 2003
RCT (178)
Control: placebo
I: age 40-75 y
E: LVEF b25%, previous TMR,
unable to do treadmill,
history cancer/proliferative diabetic
retinopathy, renal dysfunction
Death: 3% at 4 mo
ACS: 11% at 4 mo
Placebo patients underwent
intracoronary placebo injection
with no complication
Euroinject One17
phVEGF-A165, 2005
RCT (80)
Control: placebo
E: LVEF b45%, history of cancer,
proliferative diabetic retinopathy,
premenopausal women
Death: 3% at 6 mo
ACS: 15% at 6 mo
Placebo patients
underwent sham injections
(2 procedural complications
reported: STEMI and
complete AV block)
REVASC18
Ad-VEGF121, 2006
RCT (67)
Control: medical
Death: 3% at 6 mo
MACE: 26% at 6 mo
Several exclusion criteria,
including past history of cancer
AGENT III and IV21
RCT (532)
I: Angina CCS II-IV
E: age N80 y, LVEF b25%,
unprotected proximal LAD
stenosis/left main equivalent,
ICD, severe CHF, anemia unable
to do treadmill, renal dysfunction
I: age 30-75 y, angina CCS II-IV
MACE: 22% at 12 mo
Mortality rates not provided
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Jolicoeur et al 421
Table
Table
II (continued)
II (continued )
Study therapy,
year
Design (n)
Relevant inclusion/
exclusion criteria
Mortality and
morbidity in
control group ⁎
Comments
E: LVEF b30%, previous TMR,
unable to do treadmill, history
cancer/proliferative diabetic
retinopathy, renal dysfunction,
unprotected left main stenosis
Ad5FGF-4, 2007
Control: placebo
AF, Atrial fibrillation; AS, aortic stenosis; AV, auriculoventricular; COPD, chronic obstructive pulmonary disease; E, exclusion; I, inclusion; ICD, implantable cardioverter defibrillator;
LAD, left anterior descending artery; MACE, major adverse cardiac events; PAD, peripheral arterial disease; PTCA, percutaneous coronary transluminal angioplasty; RCT,
randomized-controlled trial; STEMI; ST-elevation myocardial infarction; TMR, transmyocardial laser revascularization.
⁎ACS represents all hospitalizations for unstable angina, non-STEMI, and STEMI.
reported. In recent years, several controlled trials have
explored the efficacy of alternative therapies including
laser transmyocardial revascularization9-15 and therapeutic angiogenesis.16-20 In general, these trials enrolled
patients with refractory angina despite optimal medical
therapy, so that the outcomes experienced by the
patients randomized to the control arm of these trials
may give a fair representation of the outcomes
experienced by patients with advanced CAD ( Table II).
In the control arm of these alternative therapy trials,
annual mortality rates varied from 3% to 21%, whereas
coronary events rates (including hospitalization for
decompensated angina and acute coronary syndromes
[ACSs]) varied from 11% to 69%. Of note, most of these
trials excluded patients unable to perform an exercise
treadmill test (ETT) or patients with left ventricular
ejection fraction (LVEF) b30% (detailed in Table II).
Thus, these exclusion criteria are biased toward a less
severe picture than what may actually be the case in an
unselected population of advanced CAD because
inability to perform an exercise test is associated with
increased mortality.
Registries provide additional but variable information.
The Mediators of Social Support Study reported
mortality and myocardial rates of 38% and 10%,
respectively, after a median of 2.2 years of follow-up
for patients with medically treated advanced CAD
(defined as significant 3-vessel or left main disease and
either LVEF b50% or severe angina).22 Hospitalization
occurred in 89% of patients. In the OPTions In
Myocardial Ischemic Syndrome Therapy Program
(Mineapolis Heart Intitute, Minneapolis, MN), the
largest reported prospective series of patients with
refractory angina reported, total mortality was 11.7%
after an average follow-up of 5.4 years.23 Despite the
presence of extensive CAD, cardiovascular mortality
was low (6.2%)—an annualized death rate of only 1%.
Of note, 8.3% of all the patients experienced
myocardial infarction (MI). Patients who died were
more likely to have diabetes, peripheral arterial
disease, chronic renal disease, valvular disease, history
of congestive heart failure (CHF), lower ejection
fraction, and more angina at baseline.
In aggregate, these data suggest that mortality
associated with advanced CAD is variable and depends
on multiple factors including associated comorbidities.
In addition to improving mortality and cardiovascular
events, newer therapies directed at advanced CAD
should also improve functional status and health-related
quality of life.
Contemporary treatments of
advanced CAD
Current pharmacological and nonpharmacological
therapies are outlined in Tables III and IV. Most
antianginal medications currently in use decrease myocardial oxygen demand either by limiting heart rate,
lowering systolic pressure, or by decreasing contractility.
Additional lusitropic and vasodilatory properties also
contribute significantly.
Combination of antianginal medication is often
needed to relieve refractory angina. Simple principles
may be used to enhance the efficacy of these possible
combinations. For instance, the circadian variation of
ischemic episodes shows 2 peaks (one in the early
morning and one in the late evening).25 An appropriate
chronopharmacological strategy using different preparations of extended-release nitrates or long-acting
calcium antagonists may help achieve a significantly
better therapeutic response in these critical periods of
the day.26 Orthostatic hypotension frequently limits the
total dose of antianginal medication that can be
administered to a patient. Likewise, orthostatic hypotension by itself may beget angina due to a decrease of
the coronary perfusion pressure. Simplification of the
drug regimen should be attempted whenever possible to
enhance medical adherence.
Secondary causes of angina, like anemia, poorly
controlled hypertension, thyroid dysfunction, or atrial
fibrillation with rapid ventricular rate response, should be
identified and treated accordingly.
American Heart Journal
March 2008
422 Jolicoeur et al
Table III. Contemporary treatments for chronic refractory angina: pharmacological therapies
Pharmacological
therapy
Proposed mechanisms of action
Comments
Aspirin and clopidogrel
No known antianginal effect:
prevention of thrombotic events
Warfarin may be substituted in case
of AF or decreased LVEF
β-Blockers
1.
2.
3.
4.
Selectivity to β-receptor affects antianginal properties.
Only atenolol, metoprolol, nadolol, propanolol,
and bisoprolol approved for treatment of angina
Nitrates
1. Coronary vasodilatation
2. Ventricular wall stress reduction
(↓ both pre- and postcharge)
3. Antithrombotic effect?
Tachyphylaxis development:
nitrate-free periods required
Nondihydropiridine
calcium antagonists
1.
2.
3.
4.
Especially useful when prominent
vasospastic component present
Dihydropiridine
calcium antagonists
1. Coronary vasodilatation
2. Afterload reduction (anti-HTN)
May cause reflex tachycardia: should be used in
combination to a β-blockers. Aggravation of angina
possible if severe fixed coronary obstruction
Ranolazine
1. Partial inhibition of late Na+ current (lNa)
2. Partial inhibition of fatty acid metabolism
Doubt have been emitted about action of ranolazine on
fatty acid oxidation
Statins
1. Unknown: improved endothelial function of
epicardial conductance vessels
2. ↓ coronary events
3. Plaque burden regression
Prolonged use required before therapeutic effect
Opioids 4,24
1. Direct analgesia
2. Possible decrease in adrenergic
tone with epidural analgesia
Reserved for selected patients, often as a palliative solution.
Frequent adverse events. Epidural analgesia
hampered by several side effects
Chronotrope-negative
Lusitrope-positive
Inotrope-negative
Afterload reduction (anti-HTN)
Chronotrope-negative
Lusitrope-positive
Inotrope-negative
Coronary vasodilatation
AF, Atrial fibrillation; HTN, hypertension.
Pharmacological treatments
Rationale for the administration of β-blockers, calcium
antagonists, and nitrates in refractory angina relates to
the evidence for their use in the wider population of
patients with chronic stable angina ( Table III).1,2 In
addition to this traditional pharmacopeia, newer antianginal drugs like ranolazine are now available. Antiplatelet agents and intensive dyslipidemia management
should be part of a comprehensive approach to risk
factor modification.
Antiplatelet agents combination: aspirin and
clopidogrel. Neither aspirin nor clopidogrel has intrinsic antianginal properties. Aspirin is a mandatory
component of the treatment of CAD because of its ability
to prevent atherothrombotic events.2 Several trials have
assessed whether the combination of aspirin with
clopidogrel would result in a further reduction of
coronary events. The Clopidogrel versus Aspirin in
Patients at Risk of Ischemic Events trial showed that
clopidogrel was slightly better than aspirin in preventing
vascular complications in a population of patients with
stable vascular disease.27 The Clopidogrel in Unstable
angina to prevent Recurrent Events trial demonstrated a
20% relative reduction of cardiovascular events when
clopidogrel was added to aspirin in patients with ACS.28
The Clopidogrel for High Atherothrombotic Risk and
Ischemic Stabilization, Management, and Avoidance trial
assessed whether the addition of clopidogrel (75 mg,
daily) to aspirin (75-162 mg, daily) was superior to
aspirin alone in reducing adverse cardiovascular events
in high-risk stable patients for over 4 years.29 The
combination led to a nonsignificant reduction of the
composite end point (cardiovascular death/MI/stroke)
from 7.3% in the placebo plus aspirin arm to 6.8% in
the clopidogrel plus aspirin arm (P = .22). However,
aspirin plus clopidogrel significantly increased moderate bleeding (2.1% vs 1.3%, P b .001). In a prespecified
subgroup analysis, patients with documented atherothrombotic disease at baseline did derive benefit from
clopidogrel (6.9% vs 7.9% in the placebo group,
P = .046). However, there is currently no strong
evidence for routinely combining antiplatelet therapy
American Heart Journal
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Jolicoeur et al 423
Table IV. Contemporary treatments for chronic refractory angina: mechanical treatments and advances
Nonpharmacological therapy
Proposed mechanisms of action
Comments
CTO recanalization
1. Restoration of epicardial blood flow
Success depends on technical skills and technology used
EECP
1. Diastolic augmentation + enhanced
coronary perfusion pressure
2. ↓ LV afterload
3. Release of growth factors, mobilization
of progenitor cells, ↑ NO and ↓ endothelin
Contraindications: impossible ECG gating,
decompensated heart failure, severe AI,
uncontrolled systemic hypertension, severe pulmonary
hypertension, severe lower extremity PAD,
aortic aneurysm, recent DVT
Spinal cord stimulation
1. Pain inhibition: gate control theory
2. Anti-ischemia:
a. ↓ myocardial oxygen consumption
b. Redistribution of coronary flow
c. ↓ sympathetic tone
Class A therapeutic option for refractory angina
according to ESC Joint Study Group
Heart transplantation
Organ replacement
Described indication: few cases reported
AI, Aortic insufficiency; DVT, deep vein thrombosis; ECG, echocardiogram; ESC, European Society of Cardiology; LV, left ventricle; NO, nitric oxide; PAD, peripheral arterial disease.
in patients who remain symptomatic despite optimal
medical therapy.
Statin and dyslipidemia management. Intensive
statin therapy reduces death and vascular events in
patients with established CAD.30 Whether statins have
a true anti-ischemic effect on top of usual therapy is
unknown.31 Statin-related improvement in endothelial
function provides a rationale for how angina could
be improved.32 The regression of atherosclerotic
plaque burden observed with intensive statin therapy
or with reconstituted high-density lipoprotein (HDL)
ApoA-1 Milano or with recombinant HDL has
generated hope for a reversal of symptoms in
patients with advanced CAD.33-37
Fueled by the observational studies suggesting
protection by elevated HDL, modulation of HDL
intermediate metabolism has been considered a promising target for halting progression of atherosclerosis.
In the Investigation of Lipid Level Management to
Understand Its Impact in Atherosclerotic Events trial,
however, the experimental HDL-raising drug torcetrapid (a cholesteryl-ester-transfer-protein [CETP] inhibitor) in combination with atorvastatin was associated
with an increased risk of death. Aside from the
significant increase in the blood pressure associated
with the drug, it has been speculated that the type of
HDL produced by CETP inhibition may be proatherogenic rather than antiatherosclerotic.38
Ranolazine. Ranolazine (Ranexa) is the first drug in
more than 20 years to be approved by United States
Food and Drug Administration (FDA) for the treatment
of chronic angina. The antianginal mechanisms of action
of ranolazine are not entirely known. It had been
postulated that ranolazine acted as a partial inhibitor of
fatty acid oxidation, which would facilitate energy
production in hypoxic cardiomyocytes by partially
shifting cardiac lipid oxidation to glucose oxidation.39-41
More recent studies in human cardiac myocytes indicate
this is an unlikely explanation for the antianginal/antiischemic properties because the pFOX inhibitory effect
is small at the concentrations of ranolazine used to treat
chronic angina.42
More recently, ranolazine has been found to have
electrophysiological properties similar to amiodarone,
which could explain its anti-ischemic and antianginal
properties.43 At the cardiomyocytes level, ranolazine
inhibits the late Na+ current,44 which is found to be
abnormally increased during hypoxia or in the
presence of reactive oxygen species and ischemic
metabolites.45 In experimental hypoxic conditions, this
inhibition of the Na+ current leads to an intracellular
Na+ overload,46 which activates several exchangers to
maintain cellular Na+ homeostasis. One of the most
important exchangers is the Na+/Ca++ exchanger that
transports excess Na+ out of the cell in exchange for
Ca++, resulting in abnormal intramyocyte Ca++ concentration. This abnormal Ca++ overload impairs both
the contraction-relaxation coupling and as a consequence increases diastolic tension, thereby reducing
coronary perfusion. Ranolazine, through a partial
inhibition of the late Na+ current, could limit this
pathological process and attenuate the abnormal
increase in intracellular Ca++.44
The Monotherapy Assessment of Ranolazine in Stable
Angina (MARISA) study was the first placebo-controlled
crossover trial with the sustained release preparation to
demonstrate the anti-ischemic effect of ranolazine as
monotherapy among patients with chronic severe angina.
In MARISA, a 1-week treatment of ranolazine resulted in a
dose-related increase in the exercise duration.47 In the
Combination Assessment of Ranolazine In Stable Angina
(CARISA) trial, the addition of ranolazine to standard dose
of atenolol, diltiazem, or amlodipine significantly (but
modestly) increased exercise capacity and time to
424 Jolicoeur et al
electrographic ischemia during stress testing.41 Of note,
ranolazine provided additional anti-ischemic benefits in a
setting where some of the traditional anti-ischemic agents
have failed to do so.48-50 The findings in CARISA were
confirmed by the Efficacy of Ranolazine in Chronic
Angina trial, which assessed ranolazine in patients with
persistent angina despite maximum recommended
dosage of amlodipine.51 Long-term safety information is
now available through the Ranolazine Open Label
Experience registry that followed on the MARISA and
CARISA trials.52 After 2 years, less than 10% of the patients
discontinued ranolazine because of unacceptable adverse
events: annualized death rate was of 3%. The recently
completed MERLIN trial also established the 1-year safety
record of ranolazine in a large placebo-controlled trial of
6560 patients with ACS.53
Because ranolazine exerts its antianginal effect differently than the modes of action of nitrates, β-blockers, or
calcium antagonists and has minimal effects on heart rate
or blood pressure, it is well-suited for add-on therapy in
clinically eligible refractory angina patients.41,47 This
includes patients who do not tolerate additional chronotropic- or inotropic-negative therapy.54
Opioids. Opioids are generally reserved for selected
cases of refractory angina when other therapeutic
options have failed. Under close surveillance, opioids may
be administered with reasonable efficacy and with
limited side effects.24,55 For several years, opioids have
been used with success in Denmark for the treatment of
chronic refractory angina.55 Importantly, the use of
opioids is limited by frequent side effects such as
constipation, nausea, and disorientation.56
Mechanical treatments and advances
Although highly effective for the treatment of symptomatic angina, PCI may be challenging with complex
coronary anatomy including diffuse disease and chronic
total occlusions (CTOs). Significant nonpharmacologic
advances are now being proposed to patients with
refractory angina ( Table IV).
Chronic total occlusion recanalization. By definition, a CTO of a coronary artery is present for more
than 3 months.57 Chronic total occlusions have been
identified in up to 30% of diagnostic catheterizations.58 Advances in coronary interventional techniques have enabled recanalization of CTOs with good
procedural success rates in selected cases. Although
routine opening of occluded arteries in the days
after acute MI does not reduce the occurrence of
death, reinfarction, or heart failure,59 recanalization
of chronic occlusions may improve symptoms and
possibly even the prognosis of patients with
advanced CAD.60,61
Even with the sophisticated interventional tools currently available, CTO recanalization is attempted less
frequently than it was 10 years ago. In the 7-year period
American Heart Journal
March 2008
covered by the National Heart, Lung, and Blood Institute's
(NHLBI) Dynamic Registry, the percentage of attempted
CTOs recanalization dropped from 9.6% of all PCI in 1997
to 5.7% in 2004 (P b .0001).62 The success rate of the
procedure remained stable at 71% in spite of a significant
increase in the length of lesions attempted (from 17.0 to
22.4 mm, P = .006).
In the largest reported observational study of
patients undergoing PCI for a CTO, a successful
recanalization was associated with a significant 10year survival advantage when compared with a failed
revascularization.60 In the stent era, the rate of target
vessel revascularization at 1 year after CTO recanalization has declined by approximately 50%.61 In
return, CTO attempts are associated with periprocedural complication rates exceeding 5%,60,63,64 including MI, emergency cardiac surgery, and death.
Progress in CTO recanalization is anticipated with
emerging technologies, including new tapered
hydrophilic guidewires,65 laser excimer,66 and plaque
softening formulation.67,68
Enhanced external counterpulsation. By generating precisely timed diastolic pressure augmentation,
enhanced external counterpulsation (EECP) produces
externally what aortic counterpulsation does internally.
Diastolic augmentation is accomplished with inflatable
cuffs that sequentially compress the lower limbs during
diastole and rapidly deflate before systole. This systemic
diastolic pressure augmentation increases coronary perfusion pressure, decreases ventricular afterload, and
increases venous return.69
The efficacy of EECP in patients with angina was
assessed by a single randomized sham placebo–controlled Multicenter Study of EECP (MUST-EECP).70 The
trial assessed whether a treatment regimen of 1 hour of
active counterpulsation daily for 35 days would improve
subjective angina and objective ischemia parameters
when compared with sham lower limb compression.
When compared with baseline, EECP did not increase
ETT duration but did significantly improve the time to
≥1mm ST-segment depression. Likewise, patients randomized to EECP reported an improvement of their
angina symptoms when compared with control patients.
Of note, 55% of the patients in active treatment arm
reported adverse events (such as lower limb bruise,
edema, and leg pain), but only 10% were severe enough
to cause withdrawal.
A number of hypotheses have been proposed for the
sustained antianginal effect of EECP, including a
pressure-driven recruitment of myocardial collaterals,71
hemodynamic changes, the release of proangiogenic
cytokines, and a peripheral training effect.72 The
peripheral training effect seems mediated by a
decrease in peripheral vascular resistance and a more
appropriate heart rate response to exercise.73 The
vascular shear stress provided by EECP is thought to
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Jolicoeur et al 425
Table V. Emerging therapies for advanced CAD
Therapy
Proposed mechanisms of action
Comments
Ivabradine 87
Sinus node slowing: inhibits pacemaker current (If)
Approved in Europe for patients with
chronic stable angina with sinus rhythm
and contraindication to beta-blockers.
Limited use for patient with refractory angina
Nicorandil
1. Opening of ATP-sensitive potassium channels (KATP):
dilatation of coronary resistance arterioles
2. Nitrate-like effect
3. Mimetic of ischemic preconditioning
Approved in Europe. May be use to bridge the
nitrate-free periods required to avoid tachyphylaxis
Trimetazidine
1. Mitochondrial 3-KetoAcyl CoA thiolase inhibitor
2. Shift ischemic myocardium from fatty acid to
carbohydrate use
Approved in Europe for patients with
chronic stable angina
Perhexilene
1. Mitochondrial
carnitine-palmitoyl-transferase inhibitor
2. Shift ischemic myocardium from fatty acid to
carbohydrate utilization
Serum level monitoring required due to
risk of hepatic toxicity
Therapeutic angiogenesis
(protein and gene therapy)
1. Sustained tissular expression of proangiogenic factors
2. Neovascularization
See Table VI for review of randomized control
trials of gene therapy
Cellular therapy
1. Paracrine secretion of proangiogenic factors
2. Neovascularization
3. Myogenesis (?)
Various type of cell available with additional possibility
to combine stem cell therapy and gene therapy
Thrombolytic agent
1. Depletion in fibrinogen
2. Improved blood rheology and microcirculatory flow
Urokinase administrated through intermittent dose.
Treatment never compared to placebo in a trial
Chelation therapy
1. Reduced LDL oxidation
2. PTH-related vasodilatory effect
3. Enhanced t-PA production
No direct evidence of clinical efficacy.
Transmyocardial
laser revascularization
Direct myocardial revascularization through
microchannels formation
No direct evidence of clinical efficacy
Extracorporeal cardiac shock
wave therapy
1. Cavitation effect
Efficacy and safety of SW have been reported
2. Upregulation of VEGF expression by the myocardium 88 in a phase 1 trial including 9 patients
3. Enhanced coronary angiogenesis
Neovasc reducer coronary sinus stent Controlled and permanent narrowing of
coronary sinus. Pressure-driven redistribution of
antegrade blood flow toward region of lesser resistance
First-in-man reported in 10 patients in 2006
PICVA
Evolving technology. Associated with several
procedural flaws and with high complications rates
Shunting of arterial blood into the coronary
veins with subsequent retroperfusion of capillaries
LDL, Low-density lipoprotein; SW, shock wave.
result in a systemic release of growth factors and
proangiogenic cytokines.74-76
The use of EECP is limited by the need to commit to
35 days of in-laboratory treatment. Enhanced external
counterpulsation is contraindicated in several situations
such as decompensated heart failure, severe peripheral
arterial disease, and severe aortic insufficiency. These
comorbid conditions are frequently encountered in
patients with advanced CAD. When applied to the
appropriate patient, EECP is well tolerated and associated
with low risk of adverse events.77-80
Neuromodulation. Neuromodulation includes transcutaneous electric nerve stimulation and spinal cord
stimulation. Long-term transcutaneous electric nerve
stimulation therapy is limited by electrode-related skin
irritation associated with prolonged use. Spinal cord
stimulation has been used in the past 30 years to relieve
various pain syndromes. It is now recognized as a valid
therapeutic option in Europe (class IA) for the treatment
of refractory angina.4 Modern spinal cord stimulators are
entirely subcutaneously implantable and can be installed
under local anesthesia using a minimally invasive
American Heart Journal
March 2008
426 Jolicoeur et al
Table VI. Randomized placebo-controlled trials of therapeutic angiogenesis in patients with CAD
Study
Therapy/Delivery
method
Outcomes
Safety
Comments
Laitinen et al,93 2000
(15 patients)
1000 μg
plasmid-liposome +
mouse
VEGF/IC infusion
Trial intended to assess
the effect of local VEGF
therapy on post-PCI restenosis:
no effect. Ischemia not assessed
No major serious
adverse events
reported at 6 mo
Murine gene used. Strong suspicion
of inefficient gene transfer.
Patients with advanced CAD excluded
FIRST,19 2002
(337 patients)
Ascending doses
of rFGF2/IC
No effect on ETT total
time at 90 and 180 d
5 deaths (1%) reported
in the rFGF-2 treated
patients; similar to
placebo (1%)
Angina frequency ↓ by rFGF-2
at 90 d: difference no longer
present at 180 d
Losordo et al,20 2002
(19 patients)
Ascending doses
of plasmid hDNA
VEGF-2/Transendo
Reduction in CCS angina
class significantly better in
VEGF-2 patients at 12 wk
No major serious
adverse events reported
Patients with class III or IV angina.
Trial interrupted by FDA due to a
death in an unrelated adenoviral
gene therapy trial
AGENT,94 2002
(79 patients)
Ascending doses
of Ad5-FGF4/IC
infusion
Nonsignificant trend
toward improvement of ETT
total time and time to angina
No major serious
adverse event
(mean f/u, 311 d).
One case of brain tumor
Patients with class II or III angina.
No significant dose-response effect
AGENT II,95 2003
(52 patients)
1010 pfu
Ad5-FGF4/IC infusion
Nonsignificant change in SPECT
reversible perfusion defect size
No major serious
adverse event reported
Total perfusion defect size
(necrosis + ischemia)
significantly improved with
Ad5-FGF4 (4.2% vs 0%, P = .001).
Clinically significant reduction of
angina in the active group
VIVA,16 2003
(178 patients)
rhVEGF low and high
doses/IC infusion day 0
then IV infusion
days 3, 6, and 9
No effect on ETT total time,
myocardial perfusion (SPECT)
or on angina at day 60
Significant flushing.
One case of severe
hypotension per-infusion
in high-dose group
Significant improvement of in
angina class by day 120 in the
high-dose group
KAT,96 2003
(103 patients)
2 × 1010 pfu
AdVEGF-165 vs 2 mg
plasmid-liposome
VEGF/IC infusion
Improvement in SPECT
reversible perfusion defect size
in AdVEGF group. No effect
on ETT parameter
Two new cancers
diagnosed in the
plasmid arm
Moderate angina patients (CCS 2-3).
Study designed to assess effect of
VEGF on restenosis post-PCI
Euroinject 1,17,97 2005
(80 patients)
0.5 mg of plasmid
VEGF-A165/
Transendo
No effect on SPECT reversible
perfusion defect size.
Improved regional wall motion
in the active group
NOGA procedure
related events in
5 patients
No-option patients with severe angina.
First trial to use a gene vector
(blind plasmid) as a placebo control
AGENT III
and IV,21,98 2007
(pooled analysis
532 patients)
1010 pfu vs 1011
pfu Ad5-FGF4
vs placebo/IC infusion
No effect on total ETT time.
No difference in the rate
of coronary events/death
No major serious
adverse event reported
Significant improvement in total
ETT time and reduction of angina
in women treated with either
1010 or 1011 pfu Ad5-FGF4 vs placebo
Ad, Adenovirus; f/u, follow-up; IC, intracoronary; IV, intravenous; pfu, plaque forming units; Transendo, transendocardial injection.
procedure. The therapy is self-administrated by the
patient and requires stimulation during 1 hour, 3 times a
day, and whenever angina is felt.
The analgesic effect of neuromodulation is not fully
understood but likely results from several simultaneous
mechanisms. In addition to the analgesic modulation of
A-beta neurons abnormal activity and to the restoration of
normal gamma (γ)-aminobutyric acid levels in the dorsal
horn, relief of angina may also be the consequence of
adenosine-mediated coronary vasodilatation and of
reduced sympathetic afference.81
An anti-ischemic effect has been demonstrated both
with exercise stress testing and ambulatory electrocardiogram monitoring.82
Spinal cord stimulation has been compared with
transmyocardial laser revascularization in patients with
refractory angina 83; no difference in the mean total
exercise time, angina-free exercise capacity, and Canadian Cardiovascular Society (CCS) class could be identified between the 2 groups.
Overall, spinal cord stimulation appears safe. The
initial concerns regarding a possible deprivation of a
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Volume 155, Number 3
pain warning signal, as would be the case during a
threatened MI, do not appear to be warranted.84
Animal studies even suggest that thoracic spinal cord
stimulation reduces the risk of ischemic ventricular
arrhythmias in postinfarction heart failure.85 The only
randomized placebo-controlled trial, the Stimulation
Therapy for Angina Refractory to Standard Treatments,
Interventions, and Medications trial, was prematurely
suspended in 2006. Results from this study have not
been published.86
Other therapeutic options such as thoracic epidural
anesthesia, thoracic sympathectomy, and left stellate
ganglion blockade have been associated with anecdotal
success but are rarely used because of their frequent side
effects and invasive nature.4
Emerging therapies for chronic
refractory angina
Although some of the emerging therapies presented in
the Table V are experimental, others are currently
accepted for clinical use and are gaining wider
acceptance.
Nicorandil
Nicorandil has been assessed among patients with
established CAD and recently diagnosed as having
angina during the IONA trial.89 In addition to a nitratelike effect, nicorandil opens the mitochondrial adenosine triphosphate (ATP)-sensitive potassium channels
(KATP), a property presumed to mimic the ischemic
preconditioning phenomenon. Compared with placebo,
nicorandil reduced the combined end point of cardiovascular death, non-fatal MI, and hospital admission for
cardiac chest pain (13.1% vs 15.5%, P = .014). Although
nicorandil favorably influenced death and MI in a
combined end point, neither component was improved
when taken separately. Despite its apparent clinical
benefit, nicorandil is currently not approved for use in
North America. Trial data on the efficacy of nicorandil
as an antianginal drug are inconsistent. The IONA trial
highlights issues around the FDA requirements for
approval of new antiangina medication (please see Part
II: Trial Design, End points, and Regulatory Issues). Like
many other therapies discussed in this section, nicorandil has not been specifically investigated in patients
with refractory angina; little information is available on
the safety of nicorandil in combination with traditional
antiangina therapy.
Metabolic modulation of ischemic myocardium
In contrast to the traditional antianginal agents that
operate through negative-chronotropic or negativeinotropic means, newer agents that favorably modulate
energy metabolism of the myocardium are being
developed. In normal conditions, free fatty acids are
Jolicoeur et al 427
the main source of energy for cardiomyocytes. Agents
like trimetazidine 90 and perhexiline inhibit fatty acids
β-oxidation pathways at the mitochondrial level. As a
result, in cardiomyocytes glucose metabolism is
favored over the fatty acids metabolism.91 When
compared with free fatty acids, glucose metabolism
results in a higher ATP production for the same level
of oxygen requirements; accordingly the imbalance
between oxygen level and supply takes place at higher
work loads. Metabolic modulators minimally affect
blood pressure and pulse rate so that they may be
useful in hypotensive and bradycardic patients already
on maximal traditional therapy.
Therapeutic angiogenesis
Therapeutic angiogenesis could be defined as the use of
angiogenic growth factors, genes that encode for growth
factors, or cell-based therapies to enhance the natural
process of collateral vessel development in ischemic
tissue.92 Enthusiasm for gene therapy expanded in
response to the lack of definitive efficacy of short-lived
recombinant protein therapy 16,19 ( Table VI). Unlike
protein therapy, gene therapy has the potential to induce
a sustained tissue-based expression of proangiogenic
factors. Several phase I trials established the safety of gene
therapy for patients with CAD.99 Although phase II trials
have generally been disappointing given their negative
primary end point (total exercise time or reduction of
ischemia using single-photon emission computed tomography [SPECT] imaging), some have however demonstrated a reduction in angina and an improvement in
quality of life17,20,21,96 ( Table VI).
Losordo et al20 have shown a positive effect of
vascular endothelial growth factor-2 (VEGF-2) gene
therapy in a randomized placebo-controlled trial. Using
plasmid DNA delivered by a NOGA transendocardial
delivery system (Biosense Webster, Diamond Bar, CA),
not only could they objectify a reduction of the selfreported angina in the active treatment group, but they
also were able to document a clinically encouraging
trend in exercise stress test time improvement (1.5
minutes prolongation on a Bruce protocol in the active
treatment group; P = .26). The trial was interrupted
prematurely at FDA request after a patient died from
gene therapy in an unrelated adenoviral trial. In 2003,
the Kuopio Angiogenesis Trial suggested that intracoronary adenoviral VEGF infusion was superior to plasmid
VEGF or placebo at reducing the size of SPECT
reversible perfusion defect. However, exercise stress
test parameters did not improve.96 Although encouraging, the Kuopio trial needs to be interpreted with
caution because it was primarily intended to assess the
effect of VEGF gene therapy on post-PCI restenosis.
Likewise, the variability brought by the concomitant PCI
complicates the interpretation of the anti-ischemic effect
observed in the trial.
428 Jolicoeur et al
More recently, Henry et al21 reported the analysis of the
pooled results of the Angiogenic GENe Therapy (AGENT)
III and IV trials that assessed Ad5FGF-4 in patients with
advance CAD. In the overall study population, total
exercise time was not significantly modified by the
different doses of Ad5FGF-4 when compared with
placebo. However, a prespecified analysis suggested that
women significantly benefited from the gene therapy.
The beneficial effect was consistently observed in several
angina or ischemia measures: total ETT time, time to
1 mm ST-segment depression, and CCS angina class. As
reported by the investigators, a negligible placebo in
women and a large placebo effect in men might explain
the difference observed in sexes.21
Interpretation of gene therapy should take into account
the gene, its carrying vector, and the delivery method
used.100 To date, most clinical data have been obtained
with genes encoding for different isoforms of VEGF and
fibroblast growth factor (FGF). These genes have been
selected for their potent proangiogenic capacity.101 The
choice of vectors depends on the goal of the therapy and
the admissible side effects. DNA plasmids are regarded as
safe, low-immunogenic agents; however, they have poor
transduction efficiency and result in a transitory gene
expression. Adenovirus results in more efficient transduction rates. However, adenoviruses show transient
cellular expression and provoke immunogenic reaction.102 Alternative vectors such as adeno-associated virus
and retrovirus, although endowed with attracting properties, have not yet been studied in the cardiovascular
clinical arena.100
The delivery methods currently used in clinic are
direct intramyocardial injection (either epicardial or
endocardial) and catheter-based intracoronary perfusion.
Direct injection assures an efficient albeit focal myocardial gene delivery but is invasive and may result in
major complications.17 Innovative delivery methods
such as ultrasound-targeted microbubble destruction
and coronary sinus retroinfusion may well be used soon
in clinical trials.100
Cellular therapy
Aside from their theoretical regenerative capacity,
certain cells, including endothelial progenitor cells, have
the potential to promote angiogenesis in patients with
advanced CAD. Stem cells of various types are capable of
secreting cardioprotective and proangiogenic factors to
support the development of new blood vessels when
transplanted in severely ischemic myocardium.103,104 It is
hoped that the neovascularization resulting from stem
cell transplantation will reduce the ischemic burden and
relieve symptoms like angina or heart failure.105,106
Although the clinical experience with cellular therapy
in acute MI and CHF is growing, the number of trials
directed at patients with advanced CAD remains
limited.107 The analysis of clinical trials using stem cell
American Heart Journal
March 2008
therapy in patients with refractory angina should take
into account the type of cell and the mode of delivery. In
patients with refractory angina, 3 distinct types of cell
preparations have been studied so far: skeletal myoblasts,
bone marrow mononuclear cells (BMMCs), and circulating CD34+ progenitor cells.
With the exception of the POZNAN trial,108 all of the
clinical experiments using skeletal myoblasts were
performed concomitantly with CABG surgery. Although
early phase 1 trials consistently demonstrated the
feasibility and safety of myoblast transplantation for
ischemic heart failure,109,110 proof of efficacy is still
awaited. In the first randomized placebo control Myoblast
Autologous Grafting in Ischemic Cardiomyopathy trial,
patients undergoing CABG surgery were concomitantly
transplanted with either autologous skeletal myoblasts or
placebo within their nonrevascularizable myocardial
segments. The trial was terminated prematurely after the
independent data monitoring board advised that a
therapeutic effect of skeletal myoblasts was unlikely to be
shown.111 It is generally felt that the variability brought
by a concomitant CABG surgery significantly hampered
the detection of any potential beneficial effect of skeletal
myoblasts. Skeletal muscle cells have not been assessed
properly in patients with refractory ischemia.
Bone marrow mononuclear cells are obtained from the
centrifugation of a filtered bone marrow harvest. The
BMMCs contain several subpopulations of cells, among
which hematopoietic and mesenchymal stem cells have
been shown to possess stem cell properties: They are
estimated to represent 2% to 4% of BMMCs' cellular
composition.112 In an open label trial, Perin et al113
reported a significant reduction of the reversible
ischemic defect (assessed by SPECT) among patients with
nonrevascularizable ischemia who where treated with
BMMCs using a NOGA Myostar catheter (Biosense
Webster). Four months after transplantation, BMMCs
patients have shown a significant improvement in LVEF
(from 20% to 29%, P = .003). At least one other phase I to
II trial reported similar conclusions.114
Circulating progenitor cells represent a heterogeneous
group of cells expressing the hematopoietic marker
proteins CD133, CD34, and the endothelial marker
VEGFR2. Despite the debate around the definition of
circulating progenitors cells, the clinical experience with
circulating CD34+ cells in chronic or refractory angina is
probably the most advanced. CD34+ circulating progenitor cells are usually collected from the blood after
being mobilized from the bone marrow with granulocyte
colony-stimulating factor for several days. One potential
problem with granulocyte colony-stimulating factor in
patients with advanced CAD is that it may transiently
increase angina as a result of increases in blood viscosity,
metabolic demand, and thrombocytosis.115,116 Erbs
et al117 compared the efficacy of an intracoronary
infusion of CD34+ circulating cells to a sham placebo in
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26 patients with CTO successfully recanalized. When
compared with placebo, patients treated with CD34+
circulating cells experienced a significant decline in the
number of hibernating segments in the target region.
Hence, a concordant improvement of the regional wall
motion (assessed by magnetic resonance imaging) was
observed.117 More recently, Losordo et al115 demonstrated the safety and the feasibility of injecting autologous CD 34+ cells into the myocardium using
electromechanical mapping to guide the injections
toward potentially viable regions of the left ventricle
(NOGA Myostar catheter, Biosense Webster). These
results served as the basis for a larger phase IIb trial,
which is currently under way.
Several challenges still await cellular therapy before its
clinical use is accepted. Unlike MI, advanced CAD has not
been assessed properly with randomized control stem
cell therapy trials. In the near future, genetic manipulation of stem cells either to prolong their survival 118 or to
enhance their cytokine secretion profile 119 should bring
additional hope to this already promising field.
Antioxidant and chelation therapy
In 1993, Grier and Meyers120 entitled their review
article on 37 years of ethylenediaminetetraacetic acid
(EDTA) chelation therapy, “So much writing, so little
science.” The authors came to the conclusion that,
collectively, the reported literature did not provide
reliable evidence to support a benefit of chelation
therapy in atherosclerosis. At that time, the medical
literature primarily consisted of testimonials, case
reports, and case series. Since then, no less than 5
randomized controlled trials have been designed to test
the efficacy of chelation therapy in patients with
advanced atherosclerosis.
EDTA is an amino acid complex with high affinity for
cations such as lead, magnesium, zinc, iron, and calcium.
Once in contact with EDTA, cations are chelated into an
inactive state and subsequently excreted by the kidneys.
Over the years, several putative mechanisms have been
proposed to explain how EDTA may reduce atherosclerosis progression. Current hypotheses state that EDTA
reduces low-density lipoprotein oxidation by binding
copper and iron.121 The resultant antioxidant effect is
presumed to decrease the risk of developing atherosclerosis.122,123 Indirect mechanisms involving parathyroid hormone (PTH) may also be involved. By inducing
hypocalcemia, EDTA stimulates the secretion of PTH,
which is known to relax smooth muscle cells (inhibition
of L calcium channel), induce vasodilatation, and
decrease systemic blood pressure.124,125 Other mechanisms of action, linking PTH and t-PA production, have also
been proposed.126,127
The Program to Assess Alternative Treatment Strategies to Achieve Cardiac Health trial was a double-blind,
randomized controlled trial comparing EDTA with
Jolicoeur et al 429
placebo in 81 patients with stable angina. Seven months
of EDTA administration resulted in a trivial 9-second
improvement in the exercise treadmill ischemic time
(as assessed by the time to 1 mm ST-segment deviation)
when compared with placebo. Likewise, total exercise
capacity and quality of life scores improved by similar
degrees in both groups, again suggesting an important
placebo effect.128
The Trial to Assess Chelation Therapy (TACT), sponsored by the NHLBI and the National Center for
Complementary and Alternative Medicine, is a phase III
trial currently recruiting patients in the United States.
TACT aims to randomly assign 1950 patients with recent
MI to receive 40 infusions of either the standard chelation
solution or placebo. The primary end point will be a
composite of all-cause mortality, MI, stroke, and hospitalization for angina or for CHF over a mean follow-up of
2.5 years. TACT is expected to bring a significant positive
result or an informative null result upon which rational
clinical decision making and health policy can be based.
Results are expected to be available by 2010. Although
not directly related to angina and refractory ischemia, the
TACT trial should provide important safety information
for an agent frequently used to treat refractory angina.
The risks associated with chelation therapy have been
reported to be substantial (renal failure, arrhythmia, bone
marrow depression, and even death), but the clinical
proofs of efficacy are still awaited.129
More recently, the Aggressive Reduction of Inflammation Stops Events (ARISE) study assessed the antioxidant
succinobucol (AGI-1067) in the prevention of recurrent
ischemic events on patients with recent ACS. Before
ARISE, atherosclerosis regression was demonstrated by
intravascular ultrasound using this agent.130 In ARISE,
however, succinobucol did not significantly influence the
combined end point of death, resuscitated cardiac arrest,
MI, stroke, coronary revascularization, and hospitalization for unstable angina.131
Percutaneous bypasses and retroperfusion technologies
Retroperfusion technologies exploit the coronary sinus
to redistribute either flow or pressure from the venules to
the capillaries. To date, both flow-driven retroperfusion
and pressure-driven retroperfusion have been explored in
clinical studies. Both of these techniques are the earliest
stage of development but represent important new
possibilities in the treatment of advanced CAD.
With flow-driven retroperfusion, blood from an artery
is shunted to the coronary vein that drains the ischemic
myocardial region. Using this principle, oxygenated
blood shunts through the venules and subsequently
reaches the capillaries, assuring a backward irrigation of
the ischemic myocardium. Recently, percutaneous in
situ coronary venous arterialization (PICVA) has been
attempted in patients with severe angina and no
revascularization options.132,133 This technology links
American Heart Journal
March 2008
430 Jolicoeur et al
the coronary artery proximal to its site of occlusion to
its correspondent coronary vein. The coronary sinus is
selectively occluded to permit an appropriate retrograde redistribution of the oxygenated blood to the
venules. The PICVA requires either intravascular ultrasound positioning or advanced NOGA navigation system
to be performed.
Pressure-driven retroperfusion exploits the principle
that coronary flow distribution varies according to
coronary perfusion pressure. The anti-anginal effect of a
partial occlusion of the coronary sinus has been known
for several decades.134 By selectively occluding venous
drainage of a given region of the heart, the resulting
imbalance in regional capillary pressure will lead to a
redistribution of antegrade blood toward other regions of
lesser resistance. As such, it is possible to favor blood flow
in diseased coronary segments by selectively occluding
venous drainage of other flow-competing, nondiseased
coronary segments. The Reducer (Neovasc Medical,
Israel) is a stainless steel, balloon-expandable, hourglassshaped stent that creates a selective, permanent, and
controlled narrowing of the coronary sinus. First-in-man
series reported in 2007 has shown the safety and the
feasibility of this technique.135
Conclusions
Aside for the traditional nitrates, calcium blockers, and
β-blockers, few therapies have been deemed effective to
control refractory angina. Ranolazine is the first medical
therapy approved in more than a decade for chronic
angina and should be considered in the treatment of
patients with advanced CAD. Among mechanical
therapies, EECP and transmyocardial laser revascularization are approved for the treatment of refractory angina.
Finally, CTO recanalization and metabolic modulators
have been shown to consistently relieve angina on top
of standard treatment but formal evidence of efficacy
are still lacking.
Despite these advances, many patients remain symptomatic. It is time to evaluate whether clinical programs
dedicated to these no-option patients may provide
improved care. Those clinical programs, as was the case
for heart failure clinics in the 1990s, would permit a
better characterization of the disease and improve
accessibility to sophisticated treatments. More importantly, development of these clinical programs would
accelerate our ability to provide new and innovative ways
to treat CAD in the future.
Developing new therapies for patients with advanced
coronary disease is difficult for several reasons. The
prevalence of advanced CAD is poorly defined, and the
incidence of mortality and coronary events is not known.
Because of that, selecting the appropriate trial design,
sample size, and outcomes are difficult. Additional
challenges stem from the substantial placebo effect
encountered with a subjective outcome like angina. This
has been illustrated by several trials presented in this
review, especially when therapies involving invasive
procedures were being investigated. Indeed, such a
placebo effect calls for properly blinded, sham controlled trials. In the second part of this article, we will
discuss the difficulties encountered by investigators
when designing trials for refractory angina in terms of
trial design, end point selection, and compliance with
regulatory agencies.
The authors thank Jonathan McCall for his excellent
editorial assistance.
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Appendix A
Members of the Working Group (in addition to
coauthors): Karen Alexander, MD, Duke University
Medical Center, Durham, NC; Steve C. Mockrin, PhD,
NHLBI, NIH, Bethesda, MD.
Presenters to the Working Group: Jonathan Abrams,
MD, University of New Mexico Hospital, Albuquerque,
NM; Brian Annex, MD, Duke VA Medical Center,
Durham, NC; Gregory Barsness, MD, Mayo Clinic
Rochester, Rochester, MN; Deepak Bhatt, MD, Cleveland
Clinic, Cleveland, OH; Robert Califf, MD, Duke Clinical
Research Institute, Durham, NC; Bernard R. Chaitman,
MD, Saint Louis University School of Medicine, St. Louis,
MO; Bernard J. Gersh, MD, Mayo Clinic, Rochester, MN;
David Holmes, MD, Mayo Clinic, Rochester, MN;
Timothy D. Henry, MD, Minneapolis Heart Institute,
Minneapolis, MN; Andrew Koren, MD, CV Therapeutics
Palo Alto, CA; Daniel Mark, MD, Duke Clinical Research
Institute, Durham, NC; Alice M. Mascette, MD, NIH,
NHLBI, Bethesda, MD; Magnus Ohman, MD, Duke
University Medical Center, Durham, NC; Carl Pepine,
MD, University of Florida, Gainesville, FL; Ileana Pina,
MD, Case Western Reserve University, Cleveland Height,
OH; Jyme Schafer, MPH, CMS, Baltimore, MD; Sidney
Smith, MD, University of North Carolina, Chapel Hill,
NC; Norman Stockbridge MD, PhD, FDA, Silver Spring,
MD; Anders Svensson, MD, PhD, AstraZeneca, Molndal,
Sweden; Julie Swain, FDA, CDRH, Fallbrook, CA; Robert
Temple, MD, FDA, Silver Spring, MD; Lars Wallentin,
MD, PhD, Uppsala Clinical Center University Hospital,
Uppsala, Sweden; Doug Weaver, MD, Henry Ford Health
System, Detroit, MI; Cecelia Witten, MD, PhD, FDA/
CBER, Rockville, MD; Bram Zuckerman, MD, FDA,
Rockville, MD.