Chronic%20coronary%20syndromes Treatment

• In patients with stable chest pain, it is recommended to optimize guideline-directed medical therapy in those with obstructive CAD and to optimize preventive therapies in those with nonobstructive CAD

Goals of Therapy

• Both anti-anginal therapy and treatment to reduce incidence of adverse 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 (AMI), unstable angina and cardiac 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 including risk-benefit profile 

Reduction of Incidence of Cardiac Events

Antiplatelet Agents

• Continuity of antiplatelet therapy after bleeding during treatment should be based on the bleeding severity and the proximity of the bleeding episode to the index ischemic event or percutaneous coronary intervention (PCI)  
  • To minimize ischemic risk, continue antiplatelet therapy if bleeding is within 1 month of the index event  
  • May consider reducing dose of antiplatelet, changing to less potent antiplatelets or using 1 antiplatelet agent in patients with bleeding who need de-escalation of antiplatelet therapy  
• In patients with chronic kidney disease and eGFR 15 to <60 mL/min/1.73 m² transitioning to chronic coronary syndrome (CCS), dual antiplatelet therapy (DAPT) or dual platelet inhibition (DPI) may be given; if with high bleeding risk, single antiplatelet therapy (SAPT) with Aspirin or Clopidogrel may be given  
  • In those with eGFR <15 mL/min/1.73 m², consider giving SAPT after well-tolerated DAPT of 3 months (post-PCI)  
• In elderly patients transitioning to CCS, extended DAPT (if other risk factors are present) or DPI may be given to those >75-85 years old and not frail, while SAPT may be given to frail patients >75 years old or those >80 years old 
• Aspirin
  • Antiplatelet drug of choice (cost effective)
  • 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
  • Aspirin 75-100 mg/day is recommended in patients in sinus rhythm with a prior MI or revascularization, or after stenting 
  • Aspirin dose of 75 to 162 mg/day is equally as effective as 325 mg/day in secondary prevention and is associated with a lower risk of hemorrhage
  • The addition of a second antithrombotic agent to Aspirin for long-term secondary prevention in patients without high bleeding risk should be considered in those whose risk of ischemic events is high and may be considered in those whose risk of ischemic events is at least moderately increased
  • Use the lowest effective dose to optimize the balance between therapeutic benefits and gastrointestinal side effects during chronic therapy
    • A proton pump inhibitor may be used concomitantly if risk of gastrointestinal bleeding is high

• 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
  • In addition to Aspirin, Clopidogrel (after appropriate loading dose) may be given for 6 months after coronary stenting to patients in sinus rhythm, unless the risk or occurrence of life-threatening bleeding warrants a shorter course (1-3 months)
  • A study showed that Clopidogrel demonstrated superiority over Aspirin in the secondary prevention of 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

• 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 CAD
• Statins
  • Eg Atorvastatin, Rosuvastatin, Simvastatin
  • Recommended in all patients with CCS
  • Effective in the primary and secondary prevention of coronary events and lipid management
  • Other agents which may be added to statins to achieve LDL-C targets include Ezetimibe, PCSK9 inhibitors and Inclisiran
• Please see Dyslipidemia disease management chart for further information

Angiotensin-Converting Enzyme (ACE) Inhibitors

• Recommended in all patients with SIHD who also have hypertension, DM, left ventricular ejection fraction (LVEF) of ≤40% (symptomatic heart failure or asymptomatic LV dysfunction after MI) or chronic renal disease unless contraindicated or patients at very high risk of CV adverse events 
• Reduce angiotensin II with an increase in bradykinin which decrease LV 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 ≤35% and have either diabetes or heart failure
  • May also consider giving an angiotensin receptor-neprilysin inhibitor (as a replacement to an ACE inhibitor) to patients with an LVEF ≤35% who are still symptomatic despite optimal therapy with an ACE inhibitor, a beta-blocker and a mineralocorticoid receptor antagonist (MRA)
• Exhibit cardiovascular protective effects by decreasing the risks of future ischemic events
• Similar benefits are observed in patients with IHD without LV dysfunction

Angiotensin Receptor Blockers (ARB)

• Recommended in patients with SIHD who have indications for, but are intolerant of, ACE inhibitors or angiotensin receptor-neprilysin inhibitor
• 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 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, it showed no increase in benefit and had more adverse effects
• ACE inhibitor and ARB are not usually prescribed together

Angiotensin Receptor-Neprilysin Inhibitor (ARNI)

• Findings from the PARADISE-MI trial, aiming to ascertain the efficacy of ARNI in the treatment of CAD, showed Sacubitril/Valsartan did not significantly reduce the rate of heart failure or CV death compared to Ramipril in patients with AMI
• A retrospective study showed that in patients with AMI, ARNI was superior to ACE inhibitor or ARB therapy in reducing the long-term adverse CV outcomes
  • Subgroup analysis indicated that AMI patients with LVEF <40% and <60 years old benefit more from ARNI therapy

Reduction of Ischemia and Relief of Symptoms

• Reducing symptoms and improving long-term survival are the main goals of anti-anginal therapy
• Anti-ischemic therapy should be based on patient’s BP, heart rate, LV function, comorbidities, concomitant medical therapy, adherence and preference  
  • Beta-blockers and/or calcium channel blockers are initially indicated to control heart rate and symptoms
• 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 patients with SIHD for long-term relief of symptoms
• Recommended in all patients with LV systolic dysfunction (LVEF ≤40%) with heart failure, high heart rate or prior MI, unless there are contraindications
  • In patients with reduced LV function, use should be limited to Carvedilol, Metoprolol succinate, Bisoprolol or Nebivolol which have shown to decrease the risk of death in stable optimally treated patients
• Started and continued for at least 1 year 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 the treatment of 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 
  • 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 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 CCS 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
• Dihydropyridines are recommended as the 1st step in the management of CCS in patients with low heart rate
• 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 long-term relief of symptoms when initial therapy with a beta-blocker and/or nondihydropyridine calcium channel blocker is contraindicated, poorly tolerated, causes undesirable side effects or inadequate in controlling angina symptoms 
• 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 coronary arteriolar and venous vasodilatation 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 and spray Nitroglycerin immediately relieves 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

Patients Unresponsive to Initial Therapy

• For patients who cannot tolerate, have contraindications to, or have symptoms inadequately controlled by beta-blockers, calcium channel blockers and long-acting nitrates, Ivabradine, Trimetazidine, Nicorandil and Ranolazine should be considered 2nd-line treatment agents

I_f Channel Inhibitor 

• Eg Ivabradine
• Used for symptomatic treatment of CCS 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 I_f 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
• Reported to be non-inferior to Amlodipine or Atenolol in treating ischemia or angina in patients with CCS

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

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 Factor Modification

Treat Dyslipidemia

• Goals:
  • LDL-C of <55 mg/dL (<1.4 mmol/L) and ≥50% LDL-C reduction from baseline in very high-risk patients (patients with established ASCVD)
    • For patients with ASCVD who had a 2nd vascular event within 2 years (not necessarily of the same type as the 1st) while on maximally tolerated statin-based therapy, an even lower LDL-C target level of <40 mg/dL (<1.0 mmol/L) may be considered 
  • High-density lipoprotein cholesterol (HDL-C) ≥60 mg/dL (≥1.6 mmol/L) (negative risk factor)
  • Triglyceride (TG) <150 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 include daily physical activity and weight management are strongly recommended for all 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 TG
• High-dose statin therapy that results in ≥50% reduction in LDL-C levels is recommended in the absence of contraindications or adverse effects in addition to lifestyle modifications
  • Consider combination with Ezetimibe if target goals are not achieved with maximally tolerated dose of statin
  • Consider combination with a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor for very high-risk patients who did not achieve target goals on maximally tolerated dose of statin and Ezetimibe combination therapy 
• Bile acid sequestrants, niacin, or both is an alternative for patients who cannot tolerate statins
• Therapy can be started soon after admission and continued on discharge if the patient has been hospitalized  
• Patients with TG ≥500 mg/dL (≥13 mmol/L): Niacin or fibrate should be initiated before LDL-C-lowering therapy 
• Please see Dyslipidemia disease management chart for further information

Treat Hypertension

• Goal: BP <130/80 mmHg in patients with uncomplicated hypertension, 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
• Choice of antihypertensive drugs is based on patient characteristics, indications for specific classes of drugs and comorbid illnesses
  • It may include ACE inhibitors, ARBs and/or beta-blockers, with addition of other drugs such as thiazide diuretics or calcium channel blockers if necessary to achieve optimal BP control
    • It is recommended to give beta-blockers and renin-angiotensin system blockers to post-MI hypertensive patients and beta-blockers and/or calcium channel blockers to patients with symptomatic angina 
  • ACE inhibitors or ARBs should always be included because of the renal protective effects
• Please see Hypertension disease management chart for further information

*Recommendations for BP goals may vary between countries. Please refer to available guidelines from local health authorities.

Treat Diabetes

• Goal: Should be individualized; for most adults, recommended glycosylated hemoglobin (HbA1c) goal is <7%
• Diabetes management includes lifestyle modification and pharmacological therapy to achieve the target HbA1c
  • For patients with DM and CVD, sodium-glucose linked transporter/co-transporter 2 inhibitors and glucagon-like peptide-1 receptor agonists are recommended
• Treatment of other modifiable risk factors that accompany DM such as hypertension and dyslipidemia results in a substantial decrease in cardiovascular risk
• Please see Diabetes Mellitus disease management chart for further information