Medical Care

The main goals of treatment in angina pectoris are to relieve the

symptoms, slow the progression of disease, and reduce the possibility
of future events, especially MI and premature death.
General measures
Smoking cessation results in a significant reduction of acute adverse
effects on the heart and may reverse, or at least slow, atherosclerosis.
Strongly encourage patients to quit smoking, and take an active role in
helping them to achieve this goal.
Treat risk factors, including hypertension, diabetes mellitus, obesity,
and hyperlipidemia.
Several clinical trials have shown that in patients with established
coronary artery disease, reduction of low-density lipoprotein (LDL)
level with a beta-hydroxy-beta-methylglutaryl coenzyme A reductase
inhibitor (ie, statin) is associated with significant reductions in both
mortality rate and major cardiac events. [27, 28, 29, 30]
These benefits are present even in patients with mild-to-moderate
elevations of LDL cholesterol level.
Trials with cholesterol-lowering agents have confirmed the benefits of
the therapeutic LDL lowering in older persons.
Angiographic studies demonstrate that a reduction of the LDL level in
patients with coronary artery disease could cause slowing of
progression, stabilization, or even regression of coronary artery
lesions.
One study demonstrated a significant reduction of symptomatic
myocardial ischemia in patients with unstable angina or nonQ-wave
infarction with the administration of a statin during the early acute
phase.
In a study of 10,001 patients with stable coronary artery disease, an
aggressive cholesterol-lowering approach with atorvastatin 80 mg daily
(mean cholesterol level of 77 mg/dL) compared to a less-aggressive
approach with atorvastatin 10 mg daily (mean cholesterol level of 101
mg/dL) resulted in a 2.2% absolute reduction and a 22% relative
reduction in the occurrence of a first major cardiovascular event
(defined as death from coronary heart disease; nonfatal, non
procedure-related myocardial infarction; resuscitation from cardiac
arrest; or fatal or nonfatal stroke).[31] This occurred with a greater
incidence of elevated aminotransferase levels with the aggressive
cholesterol-lowering approach (1.2% vs 0.2%, p < 0.001).
Some triglyceride-rich lipoproteins, including partially degraded very
LDL levels, are believed to be independent risk factors for coronary
artery disease. In daily practice, non-HDL cholesterol level (ie, LDL +
very LDL cholesterol [total cholesterol - HDL cholesterol]) is the most
readily available measure of the total pool of these atherogenic
lipoproteins. Thus, the ATP III has identified non-HDL cholesterol level
as a secondary target of therapy in persons with high triglyceride levels
(>200 mg/dL). The goal for non-HDL cholesterol level (for persons with
serum triglyceride levels >200 mg/dL) is 30 mg/dL higher than the
identified LDL cholesterol level goal.
Patients with established coronary disease and low HDL cholesterol
levels are at high risk for recurrent events and should be targeted for
aggressive nonpharmacological (ie, dietary modification, weight loss,
physical exercise) and pharmacological treatment.
Several large epidemiologic studies demonstrated that HDL cholesterol
levels are inversely related to cardiovascular risk. Thus, developing
pharmaceutical agents to increase the HDL level has been an
attractive target for prevention and treatment of CAD. However,
several large randomized trials utilizing cholesteryl ester transfer
protein (CETP) inhibitors did not show benefit for reducing
cardiovascular events in spite of raising HDL levels. Torcetrapib has
been one of CETP agents that has been used in large randomized
trials. [32, 33]
Investigation of Lipid level management using coronary UltraSound To
assess Reduction of Atherosclerosis by CETP inhibition and HDL
Elevation (ILLUSTRATE) was a randomized study that looked at the
effect of torcetrapib in 1188 patients with CAD who underwent
intravascular ultrasonography at baseline. [32] After treatment with
atorvastatin to reduce levels of LDL cholesterol to less than 100 mg/dL,
patients were randomly assigned to receive atorvastatin monotherapy
or atorvastatin plus 60 mg of torcetrapib daily.
Intravascular ultrasonography was repeated in 910 of these patients
(77%) after 24 months of treatment to evaluate the disease
progression. Compared with atorvastatin monotherapy, torcetrapib
atorvastatin therapy was associated with an impressive 61% relative
increase in HDL levels and a 20% relative decrease in LDL levels
resulting in an LDL to HDL ratio of less than 1.0 in this group of
patients. Despite this favorable change in the HDL and LDL levels,
among patients who underwent repeat intravascular ultrasonography,
the percent atheroma volume between the 2 groups was not different.
Torcetrapib did not result in significant decrease in the progression of
coronary atherosclerosis, but it was associated with an increase in
blood pressure.
Rating Atherosclerotic Disease change by Imaging with A New
Cholesteryl-Ester-transfer protein inhibitor (RADIANCE) 2, a trial
reported in 2007, looked into the effect of torcetrapib on carotid
atherosclerosis progression in patients with mixed
dyslipidaemia. [33] Although similar to the ILLUSTRATE trial, torcetrapib
also substantially raised HDL levels and lowered LDL levels in this
study; it did not affect the progression of carotid atherosclerosis.
Similar to the ILLUSTRATE trial, torcetrapib also significantly
increased systolic blood pressure.
Investigation of Lipid level management to Understand its iMpact IN
ATherosclerotic Events (ILLUMINATE), an international phase 3 study
of 15,000 patients, was terminated early because it had already
recorded 82 deaths in the patients taking torcetrapib-atorvastatin
compared with 51 deaths in patients taking atorvastatin alone. In
addition, the rates of MI, revascularization, angina, and heart failure
were higher in the torcetrapib-atorvastatin arm.
Due to the similar failure of multiple clinical trials focused on HDL
raising, current expert thinking about HDL is that it is to be regarded as
a marker of risk rather than as a target of therapy.
Other approaches to cardiac risk factor reduction should also be used
in combination with the above. Exercise training results in improvement
of symptoms, an increase in the threshold of ischemia, and
improvement of patients' sense of well-being. However, before
enrolling a patient in an exercise-training program, perform an exercise
tolerance test to establish the safety of such a program.
Enteric-coated aspirin at a dose of 81 mg per day should be advised
for all patients with stable angina who have no contraindications to its
use. [34, 35] In patients in whom aspirin cannot be used because of
allergy or gastrointestinal complications, consider clopidogrel. [36]
Although early observational studies suggested a cardiovascular
protective effect with the use of hormone replacement therapy, recent
large randomized trials failed to demonstrate any benefit with hormone
replacement therapy in the primary or secondary prevention of
cardiovascular disease. [37]
In fact, these studies even demonstrated an increased risk of coronary
artery disease and stroke in patients on hormone replacement therapy.
The Women's Health Initiative study demonstrated that the use of
hormone replacement therapy for 1 year in 10,000 healthy
postmenopausal women is associated with 7 more instances of
coronary artery disease, 8 more strokes, 8 more pulmonary emboli, 8
more invasive breast cancers, 5 fewer hip fractures, and 6 fewer
colorectal cancers.
Based on these data, the risks and benefits of hormone replacement
therapy must be assessed on an individual basis for each patient.
Sublingual nitroglycerin has been the mainstay of treatment for angina
pectoris. Sublingual nitroglycerin can be used for acute relief of angina
and prophylactically before activities that may precipitate angina. No
evidence indicates that long-acting nitrates improve survival in patients
with coronary artery disease. [38]
Beta-blockers are also used for symptomatic relief of angina and
prevention of ischemic events. They work by reducing myocardial
oxygen demand and by decreasing the heart rate and myocardial
contractility. Beta-blockers have been shown to reduce the rates of
mortality and morbidity following acute MI. [39] A post hoc analysis from
the ADDITIONS (prActical Daily efficacy anD safety of Procoralan In
combinaTION with betablockerS) trial demonstrated metoprolol in
combination with ivabradine for treatment of patients with stable angina
was safe and effective.[40] The investigators reported a reduction in
heart rate by 19.7 +/- 11.2 bpm, with an 8-fold decrease in weekly
angina attacks and nitrate use, accompanied by improvement in quality
of life. [40]
Long-acting heart rateslowing calcium channel blockers can be used
to control anginal symptoms in patients with a contraindication to beta-
blockers and in those in whom symptomatic relief of angina cannot be
achieved with the use of beta-blockers, nitrates, or both. Avoid short-
acting dihydropyridine calcium channel blockers because they have
been shown to increase the risk of adverse cardiac events.
Anginal symptoms in patients with Prinzmetal angina can be treated
with calcium channel blockers with or without nitrates. In one study,
supplemental vitamin E added to a calcium channel blocker
significantly reduced anginal symptoms among such patients. [41]
In patients with syndrome X and hypertension, ACE inhibitors may
normalize thallium perfusion defects and increase exercise capacity. [42]
A study by Losordo et al proposes injections of autologous CD34+
cells (105cells/kg) for patients with refractory angina. Patients who
received this experienced significant improvements in angina
frequency and exercise tolerance. [2]
Diet and activity
A diet low in saturated fat and dietary cholesterol is the mainstay of the
Step I and Step II diet from the American Heart Association.
The level of activity that aggravates anginal symptoms is different for
each patient. However, most patients with stable angina can avoid
symptoms during daily activities simply by reducing the speed of
activity.
Surgical Care
Revascularization therapy (ie, coronary revascularization) can be
considered in patients with left main artery stenosis greater than 50%,
2- or 3-vessel disease and LV dysfunction (ejection fraction, < 45%),
poor prognostic signs during noninvasive studies, or severe symptoms
despite maximum medical therapy. The 2 main coronary
revascularization procedures are percutaneous transluminal coronary
angioplasty, with or without coronary stenting, and coronary artery
bypass grafting (CABG).
Patients with 1- or 2-vessel disease and normal LV function who have
anatomically suitable lesions are candidates for percutaneous
transluminal coronary angioplasty and coronary stenting. Restenosis is
the major complication, with symptomatic restenosis occurring in 20-
25% of patients. Restenosis mostly occurs during the first 6 months
after the procedure and can be managed by repeat angioplasty.
Several trials have demonstrated that the use of drug-eluting stents
(eg, sirolimus-eluting stents, paclitaxel-coated stents) can remarkably
reduce the rate of in-stent restenosis. With the introduction of these
drug-coated stents, patients with multivessel coronary artery disease
are more frequently treated with percutaneous revascularization as
opposed to the surgical revascularization. [43, 44] More recently, some
concerns have arisen that instead of improving the long-term
prognosis, drug-eluting stents might actually worsen it. In addition,
stent thrombosis is a major concern with the useofdrug-eluting stents.
A meta-analysis of individual data on 4,958 patients enrolled in 14
randomized trials comparing sirolimus-eluting stents with bare-metal
stents looked at the long-term effect of these stents. [44] The mean
follow-up interval was 12.1-58.9 months. The primary end point was
death from any cause. The secondary end points were stent
thrombosis, the composite end point of death or myocardial infarction,
and the composite of death, MI, or a revascularization.
The overall risk of death and the combined risk of death or MI were not
significantly different for patients receiving sirolimus-eluting stents
versus bare-metal stents. A sustained reduction in the need for
revascularization occurred after the use of sirolimus-eluting stents
compared with bare-metal stents. The overall risk of stent thrombosis
with sirolimus-eluting stents was not significantly higher than bare-
metal stents. However, evidence showed an increase in the risk of
stent thrombosis associated with sirolimus-eluting stents after the first
year.
Patients with single-vessel disease and normal ventricular function
treated with percutaneous transluminal coronary angioplasty show
improved exercise tolerance and fewer episodes of angina compared
with those who receive medical treatment. However, no difference in
the frequency of MI or death has been shown between these two
groups.
The Clinical Outcomes Utilizing Revascularization and AGgressive
Drug Evaluation (COURAGE) trial looked at the benefits of PCI as an
initial management strategy in patients with stable CAD. This trial was
a randomized and involved 2287 patients who had objective evidence
of myocardial ischemia and significant CAD. [45] Of these, 1149 patients
were randomized to undergo PCI with optimal medical therapy (PCI
group) and 1138 were to receive optimal medical therapy alone
(medical-therapy group). They were observed for 2.5-7 years (median,
4.6 y). During the follow-up, no difference was reported in the primary
outcome of death from any cause and nonfatal MI between the PCI
group and the medical-therapy group. In addition, no significant
differences were noted between the 2 groups in the secondary end
points of the composite of death, MI, and stroke; hospitalization for
acute coronary syndrome; or MI.
A 2012 study was prematurely halted after it showed a significant
benefit in its primary endpoint (a composite of death, myocardial
infarction, or urgent revascularization) in patients with stable coronary
disease who underwent fractional flow reserve (FFR)-guided PCI plus
the best available medical therapy (PCI group) compared to those who
received only the best available medical therapy alone (medical-
therapy group). In this study, patients in whom at least one stenosis
was functionally significant (FFR, 0.80) were randomly assigned to
FFR-guided PCI plus the best available medical therapy or the best
available medical therapy alone while patients in whom all stenosis
had an FFR > 0.80 received the best available medical therapy. The
significant difference in primary endpoint was driven by a lower rate of
urgent revascularization in the FFR-guided PCI patients (1.6%) than in
the medical-therapy alone patients (11.1%; hazard ratio, 0.13; 95% CI,
0.06 to 0.30; P< 0.001).
Significantly fewer urgent revascularizations were triggered by a
myocardial infarction or evidence of ischemia on electrocardiography in
the FFR-guided PCI group. The authors conclude that in patients with
stable coronary artery disease and functionally significant stenosis,
FFR-guided PCI plus the best available medical therapy reduces the
need for urgent revascularization compared with the best available
medical therapy alone. In patients without ischemia, the outcome is
favorable with the best available medical therapy alone. These results
suggest a significant role for use of FFR in patients with stable
coronary artery disease to select those who might benefit from PCI. [46]
Patients with significant left main coronary artery disease, 2- or 3-
vessel disease and LV dysfunction, diabetes mellitus, or lesions
anatomically unsuitable for percutaneous transluminal coronary
angioplasty have better results with coronary artery bypass grafting.
The overall operative mortality rate for coronary artery bypass grafting
is approximately 1.3%. The rate of graft patency 10 years after surgery
is less than 50% for vein grafting, although more than 90% of grafts
using internal mammary arteries are patent at 10 years. In recent
years, interest has increased regarding surgery without
cardiopulmonary bypass (ie, off-pump) in an attempt to avoid the
morbidity associated with cardiopulmonary bypass. A recent
randomized study demonstrated that off-pump coronary surgery was
as safe as on-pump surgery and caused less myocardial damage.
However, the graft-patency rate was lower at 3 months in the off-pump
group than in the on-pump group.
Laser transmyocardial revascularization
Laser transmyocardial revascularization has been used as an
experimental therapy for the treatment of severe, chronic, stable
angina refractory to medical or other therapies. [5] This technique has
been performed with either an epicardial surgical technique or by a
percutaneous approach. In both approaches, a series of transmural
endomyocardial channels are created to improve myocardial perfusion.
The surgical transmyocardial revascularization technique has been
associated with symptomatic relief for end-stage chronic angina in the
short term. However, no published data address the long-term efficacy
of surgical transmyocardial revascularization. Nonetheless, this
technique appears to provide at least symptomatic relief for end-stage
chronic angina in the short term. [47]
Human CD34+ stem cells
A subgroup of patients with coronary artery disease experiences
angina that is not amenable to revascularization and is refractory to
medical therapy. Some studies have indicated that human CD34+
stem cells induce neovascularization in ischemic myocardium
enhancing perfusion and function.
The feasibility and safety of this treatment was tested in a recent phase
I/IIa double-blind, randomized controlled trial of 24 patients (19 men
and 5 women aged 48-84 y) with Canadian Cardiovascular Society
class 3 or 4 angina who were undergoing optimal medical treatment
and who were not candidates for mechanical
revascularization. [48] Patients received granulocyte colony-stimulating
factor 5 microg x kg(-1) x d(-1) for 5 days with leukapheresis on the
fifth day.
Electromechanical mapping was performed to identify ischemic but
viable regions of myocardium for injection of cells in the active
treatment group versus saline injection in the placebo group. The total
dose of cells was divided in 10 intramyocardial and transendocardial
injections. There was no incidence of myocardial infarction, elevation
of cardiac enzymes, perforation, or pericardial effusion. Also, there was
no incidence of ventricular tachycardia or ventricular fibrillation during
the administration of granulocyte colony-stimulating factor or
intramyocardial injections.
Serious adverse events were evenly distributed between the therapy
and the control groups. A trend was demonstrated in frequency of
angina, nitroglycerine usage, exercise time, and Canadian
Cardiovascular Society class that favored CD34+ cell-treated patients
versus control subjects given saline injections. Based on the results of
this study a larger phase IIb study is currently under way to further
evaluate this novel therapy.
Increased coronary sinus pressure
Increased coronary sinus pressure has been suggested to reduce
myocardial ischemia by redistribution of blood from nonischemic to
ischemic areas. The Coronary Sinus Reducer is a percutaneous
implantable device designed to establish coronary sinus narrowing and
to elevate coronary sinus pressure.
In a 2007 study, the safety and feasibility of the Coronary Sinus
Reducer was evaluated in 15 patients with coronary artery disease and
refractory angina who were not candidates for revascularization. [49] All
procedures were completed successfully and no procedure-related
adverse events occurred during the periprocedural and the follow-up
periods. Angina score improved in 12 of 14 patients. Also, the extent
and severity of myocardial ischemia measured by dobutamine
echocardiography and by thallium single-photon emission computed
tomography was reduced significantly (p = 0.004 [n = 13] and p =
0.042 [n = 10], respectively). This study demonstrated that the
implantable Coronary Sinus Reducers may be a feasible and safe
treatment for patients with refractory angina. Further large clinical
studies are needed before the use of these devices become an
accepted treatment.
Prevention
Coronary atherosclerosis is the main preventable cause of mortality in
the United States. A rigorous effort to address correctable risk factors
is the mainstay of preventive cardiovascular medicine.
Smoking cessation is the single most effective preventive intervention
to reduce coronary atherosclerosis prevalence. It has been associated
with a coronary artery disease reduction of 7-47% in primary
prevention settings.
Aggressive treatment of diabetes mellitus, hypertension, LV
hypertrophy, hyperlipidemia, and obesity has an important role in the
prevention of coronary artery disease.
The most important recent development in coronary atherosclerosis
risk modification is the introduction of inhibitors of beta-hydroxy-beta-
methylglutaryl coenzyme A reductase. Reductions of total and LDL
cholesterol levels by 25% and 35%, respectively, can achieve a similar
reduction in rates of total and coronary mortality, MI, and need for
coronary revascularization.