Download Modern management of chronic stable angina

Cardiology
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Modern
management
of chronic
stable angina
Treatment goals are relief of
symptoms, slowing disease
progression and improving
prognosis, write John Groarke et al
Case 1: A 72-year-old man with a history of hyperlipidaemia, hypertension and smoking presented with progressive
exertional chest tightness. An exercise stress test (EST)
was terminated at seven minutes due to chest tightness
with 2mm ST depression in leads II, V5 and V6.
Aspirin, a statin and a beta-blocker were introduced.
A diagnostic coronary angiography demonstrated a 50%
distal left main stem (LMS) stenosis, 90% ostial stenosis
of the left anterior descending (LAD) artery, and a further
50% stenosis of left circumflex artery (LCx).
He underwent three-vessel coronary artery bypass grafting (CABG) a saphenous vein graft (SVG) to the first marginal (OM1), another SVG to the first diagonal (D1) and a
left internal mammary artery (LIMA) graft to the LAD.
Case 2
A 49-year-old man with a history of smoking, hyperlipidaemia and a family history significant for ischaemic heart
disease in first-degree relatives aged less than 65 years
reported New York Heart Association (NYHA) class II dyspnoea and chest tightness.
Clinical examination revealed an ejection systolic murmur throughout the praecordium with radiation to the
right carotid. Left ventricular hypertrophy was present
on electrocardiograph (ECG). Subsequent transthoracic
echocardiography demonstrated a calcified bicuspid aortic
valve with a valve area of 0.9cm2 and a mean gradient of
60mmHg.
Diagnostic coronary angiography revealed normal coronary arteries. An aortic valve replacement was performed
to treat symptomatic severe aortic stenosis with subsequent resolution of his anginal symptoms.
Case 3
An 83-year-old woman with hypertension, hyperlipidaemia and previously stable NYHA class II angina presented
with progressive exertional chest tightness despite aspirin 75mg, atenolol 100mg and atorvastatin 20mg daily.
Episodes were easily relieved by rest and/or sublingual
nitroglycerin. Daily activities were increasingly limited by
symptoms. Coronary angiography revealed significant triple vessel disease, 100% mid-LAD occlusion, 90% stenosis proximally in a large marginal branch of LCx and a
95% stenosis proximally in a dominant right coronary artery (RCA). This lady declined CABG.
For symptomatic relief, the RCA lesion was treated with
a bare metal stent (BMS) and clopidogrel 75mg daily was
added for three months. Follow-up several years later confirmed an excellent and sustained response to percutaneous coronary intervention (PCI) with a marked reduction in
anginal frequency.
Discussion
Anginal symptoms can be presenting features of conditions other than coronary artery disease (CAD), hypertrophic
cardiomyopathy, aortic stenosis, cardiac 1 syndrome X,
tachy- and bradyarrhythmias. This review will focus on the
management of chronic stable angina due to obstructive
CAD (anginal symptoms predictably precipitated by exertion or emotion and relieved by rest or nitrate therapy).1
The annual incidence of non-fatal myocardial infarction
is between 0.5 and 2.6% in patients with chronic stable
angina.2,3 The goals of treatment are relief of symptoms,
slowing disease progression, and improving prognosis.
These goals are achieved by lifestyle modifications, pharmacological and non-pharmacological strategies.
Lifestyle modifications
Lifestyle changes (eg. smoking cessation, weight reduction, etc.) can modify specific cardiovascular risk factors.
Several trials have demonstrated a favourable impact of
exercise and diet on outcomes and disease progression in
patients with CAD.4,5,6
Optimising management of co-existing conditions that
can aggravate angina such as anaemia, hypoxaemia and
thyrotoxicosis is necessary. Drugs associated with increased
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cardiovascular risk should be avoided, eg. rosiglitazone,7
COX 2 inhibitors.
Pharmacological treatment
Angina occurs when myocardial oxygen demand exceeds
supply. Drug treatments either increase myocardial oxygen
supply or decrease oxygen demand.
Drugs used to treat angina can be grouped into two categories: anti-anginal agents and vasculoprotective agents.
Anti-anginal drugs improve symptoms and exercise tolerance, but have not been shown to prevent MI or death
in patients with chronic stable angina.1 Vasculoprotective
agents limit atherosclerosis progression and/or stabilise
atherosclerotic plaques and so improve outcome.
Anti-anginal agents
Beta-blockers
Beta-1 selective agents (metoprolol, atenolol and bisoprolol) have a more favourable side-effect profile than
non-selective beta-blockers. The dose should be titrated
up gradually to produce adequate beta-blockade: a resting
heart rate of between 50 and 60 beats per minute.
This up-titration may be limited by hypotension or other
side-effects. Inadequate dosage or dosing intervals is a
major reason for persistent anginal symptoms.
Calcium channel blockers (CCBs)
Sustained release preparations of diltiazem or verapamil,
or a second generation dihydroperidine (eg. amlodipine)
can be used as monotherapy if beta-blockers are contraindicated or not tolerated, or in combination with betablockers if anginal symptoms persist despite adequate
beta-blockade. Verapamil and diltiazem can worsen heart
failure and must be used with extreme caution in patients
with an ejection fraction of < 35%.
There are no significant differences in efficacy or outcomes reported with CCBs and beta-blockers used in the
treatment of stable angina.8 However, comorbidities such
as heart failure or previous MI would favour beta-blockers
as anti-anginal agents of choice in certain patients.
Nitrates
Sublingual nitroglycerin is used at the onset of an attack of angina to terminate symptoms or can be used as
prophylaxis immediately prior to situations known to precipitate angina. Its onset of action is within minutes and
its duration of action is less than one hour. Patients need
to be advised of administration technique and vasodilatation-mediated side-effects such as flushing, headache and
symptomatic hypotension.
Failure of symptoms to resolve following nitroglycerin
administration should be regarded as a possible acute
coronary syndrome9 and indeed the American College of
Cardiology/American Heart Association recommend that
patients contact emergency services if symptoms persist
or worsen five minutes after administration.10
Chronic nitrate administration with longer-acting preparations can reduce the frequency and/or severity of anginal
symptoms. However, nitrate tolerance can develop with
chronic administration and dosing intervals must allow for
a 12- to 14-hour nitrate-free interval each day.
Chronic long-acting nitrate therapy is largely regarded
as adjunctive therapy to beta-blockers or CCBs failing to
achieve complete symptom control. Nitrate therapy is purely
anti-anginal and does not offer any prognostic benefit.
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Other anti-anginal treatments
Ivabradine reduces heart rate by inhibiting the If channel
in the sinoatrial node. It has proven efficacy as an alternative anti-anginal agent to beta-blockers in the treatment
of chronic stable angina in patients with normal sinus
rhythm.11,12
Currently, ivabradine is predominantly used in patients
with contraindications or intolerance to beta-blockade.
Nicorandil consists of two components: a nitrate and a potassium channel opener. It is administered twice daily for
anginal prophylaxis and chronic administration can lead
to tolerance.
Vasculoprotective agents
Antiplatelet agents
All patients with chronic stable angina should receive
antiplatelet therapy in the absence of contraindications.
Aspirin is the anti-platelet agent of choice. The use of aspirin at a dose of 81-150mg per day reduces cardiovascular
morbidity and mortality by 20-25% among patients with
CAD.1
The optimal antithrombotic dosage of aspirin appears to
be between 75 and 150mg.13,14 Higher doses do not achieve
superior antiplatelet effects but do cause a higher incidence of gastrointestinal (GI) side-effects.
Clopidogrel (a non-selective ADP receptor antagonist)
can be used as the alternative antiplatelet agent in patients if there is a contraindication to aspirin therapy.15
Clopidogrel may have a slightly more favourable GI sideeffect profile than aspirin, although evidence is limited.
However, clopidogrel is significantly more expensive than
aspirin and a recent study demonstrated that the addition
of a proton pump inhibitor to low-dose aspirin therapy may
be more effective than switching to clopidogrel at preventing recurrent GI bleeding.16
Following PCI or recent MI, co-administration of aspirin
and clopidogrel will continue for a specified time period.
However, such dual antiplatelet therapy is not advocated
in patients with chronic stable angina only.13
Dipyridamole or anticoagulants (unless there is a separate indication, eg. atrial fibrillation) are not recommended
in the treatment of stable angina.
Aspirin resistance and clopidogrel resistance are the focus of much interest and research.
Statins
Major cardiovascular events are reduced in patients with
coronary artery disease treated with statins.17,18,19 Such benefits have been demonstrated even in patients with cardiovascular disease and cholesterol levels within the ‘normal’
range20,21,22 due to the pleotrophic effects (anti-inflammatory
and anti-thrombotic effects) of this drug class.
Reductions in C-reactive protein (CRP) levels with statin therapy reflect their anti-inflammatory properties.
Elevated serum CRP is associated with coronary plaque
vulnerability.23,24
Treatment of patients with CAD with higher doses of atorvastatin (80mg vs 10mg) is associated with lower rates of
cardiovascular events.25 However, higher dose atorvastatin
is associated with a higher incidence of elevations in serum aminotransferases necessitating closer surveillance of
liver (and muscle) blood tests and such high doses should
be reserved for high-risk patients.13
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Angiotensin converting enzyme (ACE) inhibitors
ACE inhibitors should be prescribed for patients with
stable angina and one or more of the following: diabetes
mellitus, hypertension, previous MI, left ventricular systolic dysfunction or proteinuric chronic kidney disease.
Who should undergo diagnostic coronary angiography?
Patients with chronic stable angina and one or more of
the following features should proceed to diagnostic coronary angiography26:
• Canadian Cardiovascular Society (CCS) class III and IV
anginal symptoms despite maximal tolerated medical
therapy
• High-risk criteria on non-invasive testing regardless of
symptom severity
• Survivors of cardiac arrests or serious ventricular
arrhythmias
• Symptoms or signs of heart failure.
For example, the patient in Case 1 above proceeded to
angiography on meeting high-risk criteria on EST while
the patient is Case 3 underwent angiography due to the
refractory nature of class III anginal symptoms to medical
therapy and an ischaemic resting ECG.
The evidence or opinion for performing diagnostic coronary angiography in other categories of patients with chronic
stable angina is less robust. Patients with CCS class I or
II anginal symptoms that respond to medical therapy and
lack evidence of ischaemia on non-invasive testing do not
require coronary angiography. Abnormal findings at coronary angiography will generally prompt the following decision: medical treatment versus revascularisation.
Revascularisation
Rapid advances in medical therapy (eg. high dose statin therapy, risk factor modification), PCI (eg. drug-eluting
stents (DES) versus BMS, dual antiplatelet therapy) and
CABG (increasing use of internal mammary arteries, radial artery grafts, minimally invasive and off-pump surgery)
limit the applicability of conclusions from earlier studies
to today’s practice. Current comparisons of these various
treatment options are under way.
Revascularisation can be achieved by either PCI or
CABG. PCI includes balloon angioplasty and stenting. A
revascularisation strategy should be considered for patients with persistent limiting angina despite optimal and
maximum medical therapy or for those with high-risk factors eg. proximal LAD or LMS, early onset of or significant
ischemia on stress testing.1,28,27
The COURAGE Trial published in 2007 compared optimal medical therapy alone or in combination with PCI
as an initial management strategy in patients with stable
coronary artery disease.
Although the addition of PCI to optimal medical therapy
reduced the prevalence of angina, it did not reduce longterm rates of death, non-fatal myocardial infarction, and
hospitalisation for acute coronary syndromes.28
The trial design was subject to criticism – DES was used
in only 15% of patients; nearly 33% of patients crossed
over from medical therapy to revascularisation during the
4.6-year follow-up period, etc.
CABG is associated with a better outcome than medical therapy for certain high-risk groups with stable angina
patients with LMS stenosis, ostial LAD or LCx lesions,
significant proximal stenosis
of all three major coronary arteries, or significant stenosis
of two major coronary arteries
including a high grade stenosis of the proximal LAD.29
This is especially true if these
lesions are associated with
impaired LV systolic function
or diabetes mellitus.
This
evidence-base
prompted the selection of
CABG over PCI and/or medical therapy for the patient
described in Case 1. Outside
of these patients with high-risk indicators proven to benefit prognostically from surgery, either PCI or surgery may
be considered as an effective option for the treatment of
symptoms.
Of course, particularly with recent advances, PCI is an
alternative to CABG in many high-risk patients described
above for symptomatic relief (eg. for patients declining
surgery) as seen in Case 3. Evidence would favour CABG as
the preferred management strategy prognostically for such
coronary disease, but the patient opted for symptomatic
relief offered by less invasive PCI.
Results of large randomised studies comparing outcomes
with modern day PCI using DES and surgery are awaited.
Although in-stent restenosis rates with DES are better than
with BMS, recently, there is concern over the higher incidence of late stent thrombosis with DES.
The ideal duration of dual antiplatelet therapy following
DES insertion is uncertain, with most centres advising dual
therapy for at least one year post insertion.30
In summary, all patients with coronary artery disease
should receive optimal medical therapy and lifestyle intervention to aggressively modify cardiovascular risk factors,
minimise anginal symptoms, limit disease progression and
improve prognosis.
Certain higher risk groups of patients should proceed to
coronary angiography. Decisions on whether revascularisation is necessary and what strategy is most appropriate
should be based on best available evidence and international guidelines of best practice. However, decisions
must be individualised and patient preference needs to be
considered.
The incidence of coronary artery disease is set to increase
as the obesity and diabetes epidemics grip the ageing population. Advances in both the medical management of and
revascularisation strategies for angina will continue.
However, randomised comparison trials to keep abreast
of these advances are necessary to guide optimal evidencebased care of the various patient groups with chronic stable angina.
John Groarke is specialist registrar in cardiology, Collette
English is registrar in cardiology, Sazzli Kasim is specialist
registrar in cardiology and Kieran Daly is consultant
cardiologist, University Hospital, Galway
References on request
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