chronic%20stable%20angina
CHRONIC STABLE ANGINA
Chronic stable angina is a clinical syndrome characterized by squeezing, heaviness or pressure discomfort in the chest, neck, jaw, shoulder, back, or arms which is usually precipitated by exertion or emotional stress and relieved by rest or Nitroglycerin.
It is caused by myocardial ischemia that is commonly associated with narrowing of the coronary arteries.
Angina is stable when it is not a new symptom and when there is no deterioration in frequency, duration or severity of episodes.

Principles of Therapy

Goals of Therapy

  • Both anti-anginal therapy and treatment to reduce incidence of cardiac events should be administered
  • Individualize treatment based on patient’s expectations and preferences
  • Relief of anginal symptoms
  • Improved chest pain-free exertion capacity
  • Prevention of subsequent acute myocardial infarction (MI), unstable angina or ischemic sudden death

Treatment Regimen

  • Should be individualized
  • Emphasize the importance of lifestyle modifications and medication adherence for managing symptoms and retarding disease progression
  • Explain medication management and cardiovascular risk reduction strategies
  • Adherence to medication regimen is more likely to be followed by a patient who is adequately counseled about their prescribed medications
    • Poor compliance can lead to increased morbidity and mortality
  • Review all therapeutic options

Pharmacotherapy

Reduction of Incidence of Cardiac Events

Antiplatelet Agents
  • Aspirin
    • Antiplatelet drug of choice to prevent coronary thrombosis
    • Aspirin should be given indefinitely in patients with ischemic heart disease (IHD) unless there are contraindications
    • Exerts antithrombotic effect by irreversibly inhibiting prostaglandin synthetase action which prevents production of platelet-aggregating substance thromboxane A2
    • Has shown to be associated with a reduction in the risk of serious vascular events which includes decrease in the risk for unstable angina and requiring angioplasty
    • Aspirin dose of 75 to 162 mg per day is equally as effective as 325 mg per day in secondary prevention and is associated with a lower risk of hemorrhage
    • Use the lowest effective dose to optimize the balance between therapeutic benefits and gastrointestinal side effects during chronic therapy
  • Clopidogrel
    • Used as an alternative drug if Aspirin is contraindicated or if patient experiences serious adverse effects from Aspirin
    • Inhibits platelet aggregation via selective and irreversible inhibition of adenosine diphosphate receptor
    • A study showed that Clopidogrel demonstrated superiority over Aspirin in the secondary prevention of myocardial infarction (MI) and death in patients with previous MI, stroke, or symptomatic peripheral artery disease (PAD)
      • However, the difference was small and no other trials have been conducted in patients with stable ischemic heart disease (SIHD)
      • Thus, Clopidogrel remains to be an acceptable alternative drug to aspirin
Lipid-lowering Agents
  • Lipid-lowering agents have shown that a decrease in low-density lipoprotein cholesterol (LDL-C) is associated with reduced risk of adverse cardiovascular events
  • Studies showed decrease in chest pain and need for revascularization in patients with stable coronary artery disease (CAD)
  • See Dyslipidemia Disease Management Chart for more details
  • Statins
    • Eg Atorvastatin, Simvastatin
    • Recommended in all patients with chronic stable angina
    • Effective in the primary and secondary prevention of coronary events and lipid management
Angiotensin Converting Enzyme (ACE) Inhibitors
  • Recommended in all patients with SIHD who also have hypertension, diabetes mellitus (DM), left ventricular ejection fraction (LVEF) of ≤40%, or chronic renal disease unless contraindicated
  • Reduce angiotensin II with an increase in bradykinin which decrease left ventricular and vascular hypertrophy, atherosclerosis progression, plaque rupture, and thrombosis
  • Aldosterone blockade with Spironolactone or Eplerenone is recommended for use in post-MI patients without significant renal dysfunction or hyperkalemia, who are already receiving therapeutic doses of an ACE inhibitor and a beta-blocker, have an LVEF ≤40% and have either diabetes or heart failure
  • Exhibit cardiovascular protective effects by decreasing the risks of future ischemic events
  • Similar benefits are observed in patients with IHD without left ventricle (LV) dysfunction
Angiotensin Receptor Blockers (ARB)
  • Recommended in patients with SIHD who have indications for, but are intolerant of, ACE inhibitors
  • Bind competitively to type 1 angiotensin II receptor which increases plasma renin activity, plasma renin, and angiotensin I and II concentration
  • Have cardiovascular protection by decreasing blood pressure (BP) equivalent to those achieved by ACE inhibitors and decrease LV mass and stroke incidences compared with beta-blockers and improve outcomes in diabetic nephropathy and heart failure
  • In a combination study of ACE inhibitor and ARB in patients with CAD or DM plus additional risk factors with no evidence of  congestive heart failure (CHF), it showed no increase in benefit and had more adverse effects
  • ACE inhibitor and ARB are not usually prescribed together

Reduction of Ischemia and Relief of Symptoms

  • Reducing symptoms and thus improving physical function and quality of life is the main goal of anti-anginal therapy
  • Medications or conditions that may provoke angina need to be investigated and treated appropriately
    • With appropriate treatment of these conditions, angina may resolve and further anti-anginal treatment may be unnecessary
    • If angina is improved but not completely resolved further therapy should be initiated
  • Anti-anginal therapy should be used in conjunction with previously mentioned therapies to improve prognosis

Beta-Blockers  

  • First-line treatment for the relief of symptoms in patients with chronic stable angina
  • Recommended in all patients with LV systolic dysfunction (LVEF ≤40%) with heart failure or prior MI, unless there are contraindications
    • Use should be limited to Carvedilol, Metoprolol succinate, or Bisoprolol which have shown to decrease the risk of death
  • Started and continued for 3 years in all patients with normal LV function after MI or acute coronary syndrome
  • Chronic beta-blocker therapy may be considered in all other patients with coronary or other vascular diseases
  • All beta-blockers appear to be equally effective in angina
  • Actions:
    • Inhibit catecholamines from binding to beta1, beta2, and beta3 receptors which decrease myocardial oxygen consumption by reducing heart rate (HR), atrioventricular nodal conduction, myocardial contractility and afterload
    • Attenuate cardiovascular remodeling by decreasing LV wall tension with long-term use
    • Reduction in HR permits more diastolic time and greater coronary perfusion enhancing myocardial oxygen supply
  • Effects:
    • Decrease angina onset with improvement in the ischemic threshold during exercise and episodes of angina
    • Improve survival and decrease recurrent MI in patients with LV dysfunction or history of MI
  • More effective than dihydropyridine calcium channel blockers in the control of angina, reduction of cardiovascular events, and need for revascularization
  • Combination therapy of beta-blockers and dihydropyridine calcium channel blockers decreases dihydropyridine-induced tachycardia by beta-blockade
    • Produces increased exercise time and capacity, and lowers the rate of cardiovascular events
    • Caution is necessary when beta-blocker is combined with Verapamil or Diltiazem because of possible bradycardia, atrioventricular (AV) block, or excessive fatigue
  • Combination therapy of beta-blocker and nitrate can be used in patients with SIHD
    • Nitrate increases sympathetic tone leading to reflex tachycardia which can be attenuated by the beta-blockers
    • Beta-blockers can increase LV wall tension associated with reduced heart rate which is counteracted by the concomitant use of nitrate
    • This combination is more effective than either monotherapy in controlling angina
  • Patients with pure vasospastic angina (Prinzmetal’s angina) without fixed obstructive lesions should not use beta-blockers because they are ineffective and may increase tendency to induce coronary vasospasm
  • Avoid abrupt withdrawal of beta-blockers because of rebound phenomenon associated with increased risk for acute MI (AMI) and sudden death
    • Taper over 1-3 week period with the use of sublingual Nitroglycerin or substitution of nondihydropyridine calcium channel blocker
Calcium Channel Blockers
  • Recommended for the relief of anginal symptoms in patients with chronic stable angina when beta-blockers are contraindicated, have adverse effects, or unsuccessful
  • Eg Dihydropyridines (eg Nifedipine, Amlodipine, Felodipine), Nondihydropyridines (eg Verapamil, Diltiazem)
  • Drugs of choice, together with nitrates, used as monotherapy or in combination in patients with Prinzmetal’s variant angina
  • Actions:
    • Noncompetitively limit calcium ion influx through voltage-dependent L-type calcium channels resulting in negative inotropic effects, cardiac pacemaker depression, slowing conduction, and smooth muscle relaxation
    • Improve myocardial oxygen supply by reducing coronary vascular resistance and augmenting epicardial conduit vessel and systemic arterial blood flow
    • Decrease myocardial demand by decreasing myocardial contractility, systemic vascular resistance, and arterial pressure
  • Effects: Decrease anginal episodes, increase exercise duration, and reduce use of sublingual Nitroglycerin in patients with effort-induced angina
  • Avoid combination treatment with Verapamil or Diltiazem and beta-blockers because of possible adverse effects on AV nodal conduction, heart rate, or cardiac contractility
Long-Acting Nitrates
  • Recommended for relief of symptoms when initial therapy with a beta-blocker or nondihydropyridine calcium channel blocker is contraindicated, causes undesirable side effects, or when additional therapy is necessary to control angina
  • Effective in the treatment and prevention of all forms of angina
    • Can also be used as monotherapy or in combination with beta-blockers in patients with Prinzmetal’s variant angina
  • Actions:
    • Both venous and arterial dilators which decrease myocardial oxygen demand by decreasing LV volume and arterial pressure via preload reduction
    • Improve oxygen supply by their vasodilatory effects on epicardial arteries and collateral vessels
    • Have antithrombotic and antiplatelet effects
  • Effects:
    • Improve exercise tolerance, time to ST-segment depression, and time to onset of angina
    • Reduce frequency and severity of angina attacks
  • Nitrates have greater anti-ischemic effect when used in combination with beta-blockers or calcium channel blockers
  • Titration of dose is important to have an adequate control of angina with the lowest possible dose to limit the occurrence of headaches and hypotension, avoid nitrate tolerance, worsening of endothelial dysfunction, and facilitate long-term adherence
  • Long-term use of nitrates may produce nitrate tolerance resulting in breakthrough angina
    • It is necessary to maintain a daily nitrate-free interval of 10-14 hours
    • Rebound angina may happen during this nitrate-free period
    • Nitrate tolerance does not develop with the sublingual route of administration and with long-acting nitrates via sublingual use
  • Strict avoidance of co-administration of phosphodiesterase inhibitors such as Sildenafil, Tadalafil, or Vardenafil within 24-48 hours of nitrate administration because of the risk of profound hypotension
  • Abrupt discontinuation of nitrates can cause increase in severity of angina
    • Severity can be reduced by concomitant administration of other anti-anginal drugs or by tapering of the long-acting nitrate dosage
Short-Acting Nitrates
  • Recommended in all patients for immediate relief of acute symptoms and/or situational prophylaxis
  • Sublingual nitroglycerin is recommended as initial therapy for exertional angina
  • Effective for prevention of effort-induced angina when administered 5-10 minutes before activity with relief lasting for 30-40 minutes
  • Actions:
    • Venodilatation and decreased diastolic filling of the heart (reduced intracardiac pressure) which promotes subendocardial perfusion
    • Coronary vasodilatation and coronary vasospasm antagonism
  • Effect: Rapid and effective symptom relief achieved with sublingual/buccal tablets or oral spray
  • Appropriate instructions on how to use short-acting Nitroglycerin is important
    • Explain to patient that it is a short-acting drug without any long-term effects and this may encourage use
  • Avoid nitrate tolerance because it blunts the response to short-acting Nitroglycerin
  •  An attack of angina that does not respond to short-acting Nitroglycerin should be regarded as a possible MI and immediate medical consultation is necessary
Xanthine Oxidase Inhibitor
  • Eg Allopurinol
  • Has anti-anginal properties
  • Studies showed decreased oxidative demand during stress or exercise
Vasodilator
  • Eg Molsidomine
  • Has anti-ischemic effects comparable to long-acting nitrates
Patients Unresponsive to Therapy

If Inhibitor
  • Eg Ivabradine
  • Used for symptomatic treatment of chronic stable angina in patients with normal sinus rhythm who have contraindications or intolerance to beta-blockers and whose heart rate is >60 beats/minute
  • Effective anti-anginal agent
  • May be used in combination with beta-blockers in patients whose resting heart rate remains high
  • Actions: Selectively inhibits cardiac pacemaker current If which controls spontaneous diastolic depolarization in the sinoatrial (SA) node
  • Effects:
    • Regulates heart rate without significant negative inotropic effect and other adverse effects associated with beta-blockers
    • Reduces heart rate and prolongs diastole thereby improving myocardial oxygen balance
    • Has no effect on BP, myocardial contractility, or intracardiac conduction parameters
    • Improves exercise capacity and decreases frequency of angina compared to patients taking Atenolol
3-Ketoacyl-CoA thiolase (3-KAT) Inhibitor
  • Eg Trimetazidine (TMZ)
  • Effective anti-anginal therapy when used as monotherapy or in combination with other anti-ischemic agents
  • Actions:
    • Inhibits 3-ketoacyl-CoA thiolase enzyme in myocardial cells which optimizes cardiac metabolism by switching energy substrate preferences from fatty acid oxidation to glucose oxidation
    • Protects the myocardium from ischemic injury which limits myocyte loss during anginal episodes
  • Effects: Increases coronary flow reserve which delays the onset of ischemia associated with exercise, improves functional capacity, decreases the frequency of angina, and reduces the need for nitrates
  •  Anti-ischemic effects are not associated with heart rate or systolic BP changes
Metabolic Agent
  • Eg L-carnitine
  • Effects: Has been observed in some patients to produce anti-anginal effects
Potassium (K) Channel Activator
  • Eg Nicorandil
  • Used for the prevention and long-term treatment of angina
  • Actions:
    • Activates adenosine triphosphate-sensitive potassium channels and promotes systemic venous and coronary vasodilation through a nitrate moiety
    • Increases coronary blood flow and decreases afterload, preload, and oxidative injury
  • Effects: Has anti-anginal and cardioprotective properties
  •  Exhibits similar anti-anginal efficacy and safety as those of beta-blockers, calcium channel blockers, and oral nitrates
  •  Tolerance can develop with long-term use
Sodium (Na) Channel Inhibitor
  • Eg Ranolazine
  • Indicated for the treatment of chronic angina
  • Can be a substitute for beta-blockers for relief of symptoms in patients with SIHD if beta-blockers are ineffective, contraindicated, or cause adverse effects
  • Can also be used in combination with other agents for SIHD
  • Good alternative drug in patients with SIHD who have bradycardia or hypotension because it has no effect on HR and BP
  • Actions: Inhibits late inward sodium current which indirectly decreases the sodium-dependent calcium current during ischemic conditions leading to improvement in ventricular diastolic tension and oxygen consumption
  • Effects: Decreases the frequency of angina, improves exercise performance, and delays the development of exercise-induced angina and ST-segment depression
  • Should only be used for patients who have not achieved an adequate response with other anti-anginal drugs because it can prolong the QT interval

Risk Factors Modification

Treat Dyslipidemia

  • Goals:
    • Low-density lipoprotein cholesterol (LDL-C) <70 mg/dL (1.8 mmol/L) or >50% LDL-C reduction when target level cannot be reached is reasonable especially in very high risk patients
    • High-density lipoprotein cholesterol (HDL-C) >38.6 mg/dL (1.0 mmol/L) for male and >46.3 mg/dL (1.2 mmol/L) for female
    • Triglyceride (TG) <65.6 mg/dL (1.7 mmol/L)
  • Assess fasting lipid profile in all patients and within 24 hours of hospitalization for those patients who present with an acute event
  • Lifestyle modifications which includes daily physical activity and weight management are strongly recommended for all ischemic heart disease (IHD) patients
    • Add plant stanol/sterols at 2 g/day and/or viscous fiber >10 g/day to further lower LDL-C
    • Take higher doses of omega-3 fatty acid (2-4 g/day) for elevated triglycerides (TG)
  • Moderate- to high-dose statin therapy is recommended in the absence of contraindications or adverse effects in addition to lifestyle modifications
  • Bile acid sequestrants, niacin, or both is an alternative for patients who cannot tolerate statins
  • Therapy can be started on discharge if the patient has been hospitalized
  • Combination therapy is beneficial for patients on lipid-lowering agents who are unable to achieve LDL-C <100 mg/dL
  • Patients with baseline LDL-C ≥2.6 mmol/L (100 mg/dL):
    • Lifestyle modification + LDL-C lowering pharmacological therapy should be initiated
    • For moderate- to high-risk patients, the intensity of therapy should be sufficient to decrease the LDL-C levels to 30-40%
  • Patients who are on LDL-C therapy and with ≥2.6 mmol/L (100 mg/dL): 
    • Pharmacological therapy should be intensified 
  • Patients with baseline LDL-C 1.8-2.6 mmol/L (70-100 mg/dL): 
    • Reduce the LDL-C to <1.8 mmol/L (70 mg/dL) 
  • Patients with TG of 5.2-13 mmol/L (200-499 mg/dL): 
    • Non-HDL-C should be <3.4 mmol/L (130 mg/dL) and further reduction of non-HDL-C to < 2.6 mmol/L (100 mg/dL) is desirable 
    • Niacin and fibrate are therapeutic options to reduce non-HDL-C after LDL-C-lowering drugs 
  • Patients with TG ≥13 mmol/L (500 mg/dL): 
    • Niacin or fibrate should be initiated before LDL-C-lowering therapy 
  • See Dyslipidemia Disease Management Chart for more details

Treat Hypertension

  • Goal: Blood pressure (BP) <140/90 mmHg in patients with uncomplicated hypertension and <140/85 mmHg in patients with diabetes mellitus (DM) and chronic renal disease
  • BP monitoring and lifestyle modification are recommended in all patients with IHD
  • Antihypertensive therapy should be initiated in addition to or after a trial of lifestyle modifications in patients with BP ≥140/90 mmHg
  • Choice of antihypertensive drugs is based on patient characteristics, indications for specific classes of drugs, and comorbid illnesses
    • It may include angiotensin converting enzyme (ACE) inhibitors and/or beta-blockers, with addition of other drugs such as thiazide diuretics or calcium channel blockers if necessary to achieve optimal BP control
    • ACE inhibitors or renin-angiotensin receptor blocker should always be included because of the renal protective effects
  • See Hypertension Disease Management Chart for more details

Treat Diabetes

  • Goal: Glycosylated hemoglobin (HbA1c) <7%
  • Diabetes management includes lifestyle modification and pharmacological therapy to achieve the target HbA1c
  • Treatment of other modifiable risk factors that accompany DM such as hypertension and dyslipidemia results in a substantial decrease in cardiovascular risk
  • See Diabetes Mellitus Disease Management Chart for more details
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