CVS

د. حسين محمد جمعه

اختصاصي الامراض الباطنة
البورد العربي
كلية طب الموصل
2012

Stable angina: drug management in primary care

Angina pectoris (commonly referred to as angina) is a clinical syndrome characterised by pain or discomfort in the chest, jaw, back, or arms. The pain may be precipitated by exertion, emotional upset, or cold weather. The prevalence of stable angina is unclear but epidemiological studies estimate 6-16% of men and 3-10% or women aged 65-74 years have had angina.

Angina is most commonly caused by coronary artery atherosclerosis; other recognised causes include:
Uncontrolled hypertension
Anaemia
Hypertrophic cardiomyopathy
Valvular heart disease
Vasospasm or endothelial dysfunction not related to atherosclerosis.
This module is concerned only with the management of angina caused by coronary artery atherosclerosis.


Stable angina is defined as angina that occurs regularly or predictably and has been occurring for more than two months. Symptoms are transient and typically provoked by exertion and relieved with rest or nitroglycerin.
Risk factors include:
Hypertension
Elevated serum cholesterol
Smoking
Physical inactivity
Overweight
Family history
Male sex
Age
Diabetes

Unstable angina is defined as anginal pain that occurs at rest or on minimal exertion, and is not relieved by nitrates or lasts more than 30 minutes.
• Recent onset angina, an
• accelerating pattern of previously stable angina
• postmyocardial infarction angina, and
• angina after a revascularisation procedure are also considered to be unstable. Unstable angina is thought to be due to plaque thrombosis and constitutes a medical emergency.

Learning bites

Chest pain that occurs at rest or at night is well described in patients with stable angina, especially in women.
Atypical presentations of angina are more common in women than in men. Women are more likely to report inframammary pain, sharp pain, or variable pain thresholds.
Atypical presentations are also more common in elderly people and those with diabetes (these patients are more likely to have silent ischaemia).


Patients with suspected angina should have a detailed initial clinical assessment that includes history, examination, and an assessment of blood pressure, haemoglobin, thyroid function, cholesterol, and glucose levels.

The aims of treating angina are to:

• Relieve symptoms
• Prevent or slow disease progression
• Prevent future cardiac events
• Improve survival and quality of life.

Drug therapy for immediate symptom relief

Short acting nitrates
Action
The primary anti-ischaemic effect of nitrates is to decrease myocardial oxygen demand by producing systemic vasodilatation more than coronary vasodilatation.
This decreased myocardial oxygen demand relieves the symptoms of an acute anginal attack.

Side effects

The most common side effects of nitrates are headache and flushing. Postural hypotension may also occur.
Sublingual nitroglycerin is the therapy of choice for acute anginal episodes and prophylactically for activities known to elicit angina, such as mowing the lawn, playing tennis, or walking in cold weather.

Dose

Sublingual 0.2-0.6 mg tablet or one or two sprays of glyceryl trinitrate spray every five minutes for a maximum of three doses in 15 minutes. Note that these must be discarded eight weeks after they are opened.
Contraindications
• Patients who have taken sildenafil within 24 hours (risk or severe hypotension)
• Patients with hypertrophic cardiomyopathy (risk or increased outflow tract obstruction)


Single agent therapy is advised as first line for preventing symptoms. In patients whose symptoms are not controlled on a single agent, dual therapy with an agent from another class would be appropriate. Although other drug classes have similar efficacy, beta blockers are first line treatment for patients with chronic stable angina (in the absence of contraindications).
Learning bite
Consider aspirin as part of the initial regimen
Drug therapy for preventing symptoms

Beta blockers

Action
Beta blockers prevent exercise related increases in heart rate and contractility, which can trigger anginal symptoms. Also, high risk patients (for example, those postmyocardial infarction in a randomised controlled trial) who take beta blockers reduce their cardiovascular mortality and morbidity. Cardioselective beta blockers are most commonly used in patients with stable angina.
Side effects
Bradycardia .Bronchospasm.Exertional tiredness
Sleep disturbance. sexual dysfunction and cold peripheries

Cautions

Patients with asthma should not take beta blockers because they can cause bronchospasm. You should warn patients that acute withdrawal of beta blockers is associated with an increase in coronary events. If necessary, they should be withdrawn gradually over several weeks.
Evidence
There is a lack of good quality, randomised, controlled trial evidence to support the use of beta blockers as first line therapy over other drug classes. However, trials comparing beta blockers with placebo confirm their efficacy in reducing symptoms.

The consensus opinion is that in view of their beneficial effects on cardiovascular mortality, you should offer beta blockers as first line treatment unless they are contraindicated.
Dose
Atenolol 50-100 mg daily (may increase to 100 mg daily) or
Bisoprolol 5-10 mg daily.


Learning bite
Although beta blockers have been shown to reduce symptoms and development of myocardial ischaemia in stable patients, they have not been shown to reduce mortality in these patients unless they have myocardial infarction or heart failure associated with a reduction in left ventricular systolic function.

Long acting nitrates

Action
Oral long acting preparations of nitrates are effective for treating the symptoms of stable angina by reducing myocardial oxygen demand. Patch preparations are also available but are significantly more expensive than tablets.
Side effects
The main side effects are headache and postural hypotension. These can be minimised by starting with a low initial dose.

Cautions

Nitrates should be avoided in patients with aortic stenosis. In patients with suspected right ventricular infarction, nitrates should be avoided, if possible, because of the increased risk of inducing hypotension.
Tolerance to nitrates is quick to develop. When you prescribe nitrates you should allow a nitrate free period of six to eight hours per day.

Evidence

Both isosorbide dinitrate and mononitrate have been shown in controlled trials to be more effective than placebo at controlling angina. But there is insufficient evidence to recommend nitrates over other antianginal drug classes.
Dose
You can give isosorbide mononitrate 20-60 mg twice daily

Learning bite

Tolerance to nitrates as treatment for chronic angina is a major problem. Although several strategies have been attempted to prevent nitrate tolerance, the most effective has been intermittent therapy with an adequate nitrate free interval. However, patients may have rebound angina during this nitrate free interval. Chronic nitrate therapy is used to prevent recurrent anginal episodes, but must be dosed correctly to prevent tolerance.


Calcium antagonists
Action
Calcium antagonists block the initial calcium influx into the myocytes and vascular smooth muscle cells causing coronary and peripheral vasodilatation, decreased atrioventricular conduction, and reduced contractility. This reduces myocardial oxygen demand reducing the symptoms of chronic stable angina.

Verapamil is a negative inotrope that also slows the sinus rate and decreases atrioventricular conduction. It is a much less potent vasodilator than the dihydropyridines .
Diltiazem is a modest vasodilator and has modest negative inotropic and chronotropic effects
The dihydropyridines have a greater selectivity for vascular smooth muscle than myocardium, they are therefore more potent vasodilators with less effect on contractility and atrioventricular conduction .

Side effects

Symptomatic bradycardia
Heart block
Worsening heart failure
Constipation
Flushing
Headache
Dizziness
Pedal oedema.
Constipation is the most common side effect of verapamil.

Learning bite

You should generally avoid verapamil and diltiazem in patients with heart failure because they can depress myocardial function. These two drugs can also cause severe bradycardia. Long acting dihydropyridines (eg amlodipine) can be used in heart failure.


Cautions
When combined with a beta blocker there is a risk of bradycardia with rate limiting calcium antagonists. Calcium channel blockers such as amlodipine are contraindicated in patients with aortic stenosis.
Short acting forms of nifedipine are contraindicated in patients with angina; they can cause a reflex tachycardia and large variations in blood pressure.

Evidence

There is a consensus view that calcium channel blockers are effective for treating symptoms of stable angina. No significant difference has been found between calcium channel blockers and beta blockers in terms of symptom control.
Dose
You should prescribe long acting calcium channel blockers (such as diltiazem) by proprietary brand name because significant variation in bioavailability may occur between preparations.
The dose of amlodipine is 5-10 mg per day.

Learning bite

Long acting calcium channel blockers, such as amlodipine, are appropriate agents for patients with coronary artery vasospasm. You should avoid short acting dihydropyridines, such as nifedipine, because of the risk of a negative inotropic effect, marked hypotension, and reflex increase in sympathetic activity.

Other medications

Potassium channel openers
Nicorandil reduces preload and afterload and increases coronary blood flow, thereby relieving angina.
Side effects
Headache and dizziness
Evidence
There have been no randomised controlled trials of long term single drug treatment of angina with potassium channel openers.
Dose
10-20 mg twice a day


ACE inhibitors
There is good quality evidence to suggest that all patients with stable angina should be considered for treatment with ACE inhibitors.
Evidence
The question of whether patients with stable angina but without left ventricular systolic dysfunction benefit from ACE inhibitors has been controversial. Although results from four large randomised controlled trials that address this topic have given conflicting results, when re-analysed in two meta-analyses of these and other trials, ACE inhibitors significantly reduced all cause and cardiovascular mortality.

Reducing cardiac risk with non-drug measures

Smoking
A systematic review of smoking cessation for secondary prevention of coronary artery disease suggested a 36% risk reduction in total mortality. There is good evidence that advice and interventions including counselling, nicotine replacement, and bupropion can increase rates of smoking cessation.
Learning bite
Bupropion can cause seizures. You should avoid it in patients with a history of seizures or in those who have a predisposition to seizures .

Diet

All patients with angina should be advised to have a healthy diet. Diet contributes to several risk factors for cardiovascular disease including hypercholesterolaemia and obesity. Evidence from studies of patients who have had a myocardial infarction suggests that dietary change, in particular a Mediterranean diet, can reduce the risk of further cardiac events.

Antioxidant vitamin combinations

There is no evidence to suggest that antioxidant combinations (beta carotene, vitamin C, tocopherol, vitamin E) are more effective at reducing cardiovascular events than placebo.
Learning bite
Antioxidant vitamins (such as vitamin E, beta carotene, and vitamin C) do not appear to have any effect on cardiovascular events in high risk people, and in some cases may increase the risk of cardiac mortality.

Obesity

You should encourage patients with angina to reduce their body mass index to <25 kg/m2 if they are overweight. Obesity increases myocardial oxygen demand in addition to the adverse effects on blood pressure, cholesterol, and glucose tolerance.


Physical activity
Physical activity increases exercise tolerance in patients with stable angina. Randomised controlled trials have demonstrated a reduction of objective measures of ischaemia in patients with chronic stable angina undertaking physical activity. Recommendations should take into account individual patients' overall risk profile.2

In general, patients should start slowly and exercise for about 20 minutes and increase this as their symptoms allow.
One recent study stated that "compared with angioplasty, a 12 month programme of regular physical exercise in selected patients with stable coronary artery disease resulted in superior event free survival and exercise capacity at lower costs, notably owing to reduced rehospitalisations and repeat revascularisations."

Reducing cardiac risk with drug therapy

Aspirin
Benefits
used for secondary prevention of cardiovascular events.
Side effects
The most common side effect of aspirin is dyspepsia. This occurs more often at higher doses.
Evidence
Randomised controlled trials have demonstrated that aspirin is associated with a significant reduction in cardiovascular events in patients with stable angina. Meta-analysis has shown that higher dosages (>75 mg) confer no additional benefit on risk reduction.

Learning bite

Compared with placebo, statins (HMG-CoA reductase inhibitors) reduce mortality at three to six years in people at high risk of cardiovascular events, although the benefits may be greater in men than in women. There is good evidence to suggest that all patients with stable angina due to atherosclerotic disease should receive long term standard aspirin and statin therapy.

Benefits

You can use statins in addition to dietary measures to reduce total cholesterol and slow the atherosclerotic process in coronary vessels. Traditional advice was to measure cholesterol levels of patients with angina and to try to reduce the level if total cholesterol is 5.0 mmol/l or more. But the Heart Protection Study showed that the benefits of cholesterol reduction in established vascular disease accrue below the old threshold level of 5.0 mmol/l.
Side effects
Reversible myositis is a rare but important side effect of statins. They can also cause headache, elevated liver function tests, and gastrointestinal side effects.


Evidence
Randomised controlled trials have shown that statins for the secondary prevention of coronary heart disease reduce the risk of cardiac events.
The absolute benefit over several years of lowering cholesterol is greatest in people with the highest baseline risk of an ischaemic cardiac event
It is unclear whether any one statin has advantages over the others .
Dose
Several statins are available. A standard dose of simvastatin is 40 mg daily.

Learning bite

Untreated hypothyroidism and renal failure increase the risk of statin induced myositis.
Hormone replacement therapy
Contrary to decades worth of large observational studies, many randomised controlled trials show no cardiovascular benefit from oestrogen with or without progesterone in postmenopausal women. In one randomised controlled trial, more women in the group taking hormone replacement therapy experienced venous thromboembolism and gall bladder disease than in the placebo group.

Elevated levels of biomarkers such as C reactive protein and brain natriuretic peptide have prognostic value in patients with stable angina. But the clinical usefulness of these tests has yet to be determined.

In the past it was possible to stratify only patients who were able to perform physical activity (such as walking on a treadmill). But now other techniques are available for patients who are unable to exercise adequately. These include dobutamine stress echocardiography and myocardial perfusion imaging.

Stable angina

beta blockers such as bisoprolol first line .
Nicorandil is a second line agent.
Nitrates are second line agents.
Amlodipine is a second line agent.


More than half of patients with stable angina will have a normal resting ECG.
Of all the calcium channel blockers verapamil is most notorious for causing constipation and gingival hyperplasia.