Stable Ischemic Heart Disease (SIHD) PDF

Stable Ischemic Heart Disease (SIHD) Introduction  Also called coronary heart disease (CHD) or coronary artery disease (CAD)  The term ischemic refers to a decreased supply of oxygenated blood to the heart muscle  It is caused by stenosis, or narrowing, in one or more of the major coronary ar...

Stable Ischemic Heart Disease (SIHD) Introduction  Also called coronary heart disease (CHD) or coronary artery disease (CAD)  The term ischemic refers to a decreased supply of oxygenated blood to the heart muscle  It is caused by stenosis, or narrowing, in one or more of the major coronary arteries that supply blood to the heart, most commonly by atherosclerotic plaques  Atherosclerotic plaques may impede coronary blood flow to the extent that cardiac tissue distal to the coronary artery narrowing is deprived of sufficient oxygen to meet oxygen demand  It results from an imbalance between myocardial oxygen supply and oxygen demand Clinical manifestations: 1. Chronic stable angina  the most common 2. Acute coronary syndromes (ACS): Non-ST-segment elevation ACS: myocardial infarction (NSTEMI) or unstable angina ST-segment elevation myocardial infarction (STEMI) EPIDEMIOLOGY AND ETIOLOGY  The leading cause of death for both men and women in the United States  Incidence is higher in middle-aged men compared with women  The incidence rate increases 2-3x in women after menopause  Chronic stable angina is the initial manifestation of IHD in about 50% of patients  ACS is the first sign of IHD in other patients Conditions Associated with Angina Causes of angina: 1. Atherosclerosis:  The major cause of angina  Leads to obstructive lesions in one or more of the major coronary arteries or their principal branches  Vasospasms at the site of an atherosclerotic plaque  constrict blood flow and contribute to angina Causes of angina: 2. Nonatherosclerotic  Less common  Vasospasm in coronary arteries with no or minimal atherosclerotic disease  Can precipitate ACS  Other causes are in the next table Risk Factors  Patients with multiple risk factors, particularly those with DM, are at greatest risk for IHD  5-7x higher risk compared to individuals without risk factors  Optimization of modifiable risk factors can significantly reduce risk of myocardial infarction (MI) Modification of risk factors is among the primary strategies for delaying IHD progression and preventing IHD-related events including death  Risk Factors Risk factors (are associated with endothelial damage and dysfunction and contribute to the development of atherosclerosis):  HTN  DM  Dyslipidemia  Cigarette smoking  Physical inactivity and obesity independently increase the risk for IHD, in addition to predisposing individuals to hypertension, dyslipidemia, and diabetes Pathophysiology Pathophysiology A. Causes of increase in myocardial oxygen demand: Increases in heart rate, cardiac contractility, and left ventricular wall tension increase the rate of myocardial oxygen consumption (MVO2)  Ventricular wall tension is a function of:  Blood pressure (BP)  Systemic vascular resistance  Left ventricular end-diastolic volume  Ventricular wall thickness  Physical exertion increases MVO2 and commonly precipitates symptoms of angina in patients with significant coronary atherosclerosis Pathophysiology B. Causes of reduction in myocardial oxygen supply 1. Reduction in coronary blood flow:  Atherosclerotic plaques  Vasospasm  Thrombus formation 2. Reduction in arterial oxygen content (due to hypoxia) 3. Decrease in diastolic filling time (e.g, tachycardia) 4. Decrease in myocardial oxygen delivery with adequate coronary perfusion  Anemia, Carbon monoxide poisoning, Cyanotic congenital heart disease A. Coronary Atherosclerosis Endothelial damage and dysfunction (commonly caused by HTN, DM, and smoking)  allow LDL cholesterol and inflammatory cells (eg, monocytes and T lymphocytes) to migrate from the plasma to the subendothelial space 1. Monocyte-derived macrophages ingest lipoproteins to form foam cells 2. Macrophages also secrete growth factors that promote smooth muscle cell migration from the media to the intima 3. Resulting in the development of early atherosclerosis in the form of a fatty streak consisting of lipid-laden macrophages and smooth muscle cells 4. The fatty streak enlarges as foam cells, smooth muscle cells, and necrotic debris accumulate in the subendothelial space A. Coronary Atherosclerosis 5. A collagen matrix forms a fibrous cap that covers the lipid core of the lesion to establish an atherosclerotic plaque 6. The plaque may progress until it protrudes into the artery lumen and impedes blood flow When the plaque occludes ≥ 70% of a major coronary artery or ≥ 50% of the left main coronary artery  the patient may experience angina during activities that increase myocardial oxygen demand Stable Versus Unstable Atherosclerotic Plaques SIHD vs. ACS The hallmark feature of SIHD an established atherosclerotic plaque in ≥ 1 of the major coronary arteries that impedes coronary blood flow The hallmark feature of ACS an atherosclerotic plaque that ruptures with subsequent thrombus formation Plaque rupture: fissuring of the fibrous cap and exposure of the plaque contents to elements in the blood Plaque composition, rather than the degree of coronary stenosis, determines the stability of the plaque and the likelihood of rupture and ACS Microvascular angina  Compared with men, women with angina are more likely to present with microvascular disease  Also called cardiac syndrome X  Refers to disease of the smaller coronary vessels  Causes typical angina in the absence of obstructive CAD of the epicardial arteries  Associated with:  Endothelial dysfunction  Reduced smooth muscle relaxation Resulting in reduced vasodilation and enhanced vasoconstriction B. Coronary Artery Vasospasm  Also called prinzmetal or variant angina  Results from spasm (or vasoconstriction) of a coronary artery in the absence of significant atherosclerosis  Usually occurs at rest, especially in the early morning hours  Vasospasm is generally transient, but may persist long enough to cause myocardial ischemia and subsequent infarction  Patients are younger than those with chronic stable angina  Patients often do not possess the classic risk factors for IHD  The cause of variant angina is unclear but may involve vagal withdrawal, endothelial dysfunction, and paradoxical response to agents that normally cause vasodilation B. Coronary Artery Vasospasm  Precipitants: Cigarette smoking Cocaine or amphetamine use Hyperventilation Exposure to cold temperatures  Management: Should distinguish between this and IHD Management of the two is not mutually exclusive CLINICAL PRESENTATION AND DIAGNOSIS  Patients may present with typical symptoms of angina, atypical symptoms of angina, or a combination of both  Identification of an atypical presentation is vital as some individuals with IHD may present without any of the classic symptoms of angina 1. Angina pectoris (angina) The most common symptom of IHD It is discomfort in the chest that occurs when the blood supply to the myocardium is compromised  CLINICAL PRESENTATION AND DIAGNOSIS  Chronic stable angina Chronic occurrence of chest discomfort due to transient myocardial ischemia with physical exertion or other conditions that increase myocardial oxygen demand The most common manifestation of stable IHD (SIHD) o Because the pathophysiology of SIHD is due primarily to increases in oxygen demand rather than acute changes in oxygen supply, symptoms are typically reproducible when provoked by exertion, exercise, or stress o The exception may be a patient with coronary artery vasospasm, in whom symptoms may be more variable and unpredictable Chronic stable angina should be distinguished from UA because the latter is associated with a greater risk for MI and death and requires hospitalization for more aggressive treatment CLINICAL PRESENTATION AND DIAGNOSIS  ACS: Generally, occurs in response to an acute decrease in coronary blood flow leading to inadequate oxygen supply So, it is marked by prolonged symptoms, often occurring at rest, or an escalation in the frequency or severity of angina over a short period of time Physical Findings and Laboratory Analysis  Glycemic control (ie, fasting glucose, hemoglobin A1c)  Fasting lipids  Hemoglobin  Organ function (ie, BUN, SCr, LFTs, TFTs)  Findings such as carotid bruits, abdominal and/or renal bruits, or abnormal peripheral pulses indicate atherosclerosis in other vessel systems and raise suspicion for IHD Diagnostic Tests 1. Resting 12-lead ECG 2. Cardiac troponin  o To distinguish between MI (elevated cardiac troponin) and either UA or noncardiac causes of chest discomfort (normal cardiac troponin) o For patients with ACS, serial measurements of cardiac troponin (usually 2–3 measurements over a period of 3–12 hours) are performed to exclude the diagnosis of an acute MI o Cardiac findings on the physical examination are often normal in patients with SIHD 3. “Stress” testing with either exercise or pharmacologic agents  increases myocardial oxygen demand  to evaluate the patient with suspected IHD 4. Coronary artery calcium scoring via computed tomography (CT) 5. Coronary angiography (cardiac catheterization or “cardiac cath”) Treatment Desired Outcomes 1. Prevent ACS and death 2. Alleviate acute symptoms of angina 3. Prevent recurrent symptoms of angina 4. Prevent the progression of the disease 5. Reduce complications of IHD 6. Avoid or minimize adverse treatment effects General Approach to Therapy of SIHD Primary strategies for preventing ACS and death (eg, primary or secondary prevention) are to:  Aggressively modify cardiovascular risk factors  Slow the progression of coronary atherosclerosis  Stabilize existing atherosclerotic plaques  4 1 The goal of therapies that alleviate and prevent angina is: improving the balance between myocardial oxygen demand and supply. 3 2 Drug treatment for angina is primarily used to reduce oxygen demand Non-pharmacological:  1. Lifestyle Modif ications 1. Smoking cessation 2. Dietary modifications Limit cholesterol intake to < 200 mg/day. Limit consumption of saturated fat to < 7% and trans fatty acids < 1% of total calories Limit daily sodium intake to < 1500 mg for BP control Limit alcohol consumption to one drink/day for women and one to two drinks/day for men unless otherwise contraindicated 3. Increase physical activity 4. Weight loss Non-pharmacological:  2. Interventional Approaches to Revascularization Revascularization by PCI and coronary artery bypass graft (CABG) surgery effectively restore coronary blood flow, improving myocardial oxygen supply  A. Percutaneous Coronary Intervention (PCI), when: performed to restore coronary blood flow and relieve symptoms Optimal medical therapy fails Symptoms are unstable Extensive coronary atherosclerosis is present (eg, > 70% occlusion of coronary lumen) Non-pharmacological:  2. Interventional Approaches to Revascularization  Drug-eluting stents (DES) are impregnated + low concentrations of an antiproliferative drug (paclitaxel, everolimus, sirolimus, or zotarolimus)  released locally over a period of weeks to inhibit in-stent restenosis of the coronary artery after PCI  Rotational atherectomy may be performed (a special catheter is used to essentially cut away the atherosclerotic plaque)  to restore coronary blood flow B. Coronary Artery Bypass Graft Surgery (open heart surgery): if the patient has extensive coronary atherosclerosis (> 70% occlusion of ≥ 1 coronary arteries) or is refractory to optimal medical treatment Pharmacologic therapy 1. Risk Factor Modif ication: Recommendations  Statins and ACEis  possess vasculoprotective effects (e.g, anti-inflammatory effects, antiplatelet effects, improvement in endothelial function, and/or improvement in arterial compliance and tone)  ARBs  alternative to ACEis as discussed previously  Antiplatelet: Adding aspirin  reduce the risk of acute coronary events and death in patients with SIHD Dual antiplatelet therapy (DAPT)  aspirin + P2Y12 antagonist  for patients with IHD (following hospitalization for ACS ± percutaneous coronary intervention [PCI] and/or following intracoronary stent placement)   to reduce ischemic events  β-Blockers  decrease morbidity and improve survival in patients who have suffered an MI (esp. patients with concomitant HFrEF). A. Dyslipidemia  Statins are the mainstay of therapy should be considered in all patients with SIHD regardless of baseline LDL cholesterol Particular benefit in those with elevated LDL cholesterol or DM  Lowering cholesterol with statins reduces the risk of MACE by 22% for each 39 mg/dL (1.01 mmol/L) of LDL cholesterol reduction  Improve endothelial function and vascular tone by reducing smooth muscle cell proliferation and enhancing vasoactive response of the coronary arteries  Inhibit inflammation and oxidative stress by lowering C-reactive protein and other inflammatory mediators implicated in atherosclerosis  Improve atherosclerotic plaque stability via macrocalcification and increased fibrous cap thickness  Reduce platelet aggregation by decreasing platelet reactivity and TXA2 synthesis Recommendations for treatment of dyslipidemia in patients with IHD include: 1. High-intensity or maximally tolerated statin  in very high-risk patients with ASCVD (as defined by a history of multiple major ASCVD events or one major event and multiple high-risk conditions 2. High-intensity statin  in patients ≤ 75 years of age with ASCVD who are not considered very high-risk If not tolerated  a moderate-intensity statin can be used 3. Moderate- to high-intensity statin therapy  for patients > 75 years of age with ASCVD who are not considered very high risk 4. Consider adding ezetimibe  in individuals with clinical ASCVD on maximally tolerated statin therapy with LDL cholesterol ≥ 70 mg/dL (1.81 mmol/L) 5. Consider adding PCSK9 inhibitors  in patients on maximally tolerated LDL-lowering therapy (maximally tolerated statin and ezetimibe) with LDL cholesterol ≥ 70 mg/dL (1.81 mmol/L) or non-high-density lipoprotein (non-HDL) cholesterol ≥ 100 mg/dL (2.59 mmol/L) B. HTN  Aggressive identification and management of HTN are warranted in patients with SIHD to minimize the risk of MACE  Patients with SIHD and a BP of ≥ 130/80 mm Hg  should be started on antihypertensive therapy to reduce BP to a target of < 130/80 mm Hg  Selection of initial agent is guided by the presence of compelling indications (eg, chronic stable angina, HFrEF, previous MI)  In the absence of contraindications, ACE inhibitors should be considered in all patients with SIHD, particularly those individuals who also have:  HTN, DM, CKD, Left ventricular dysfunction, History of MI, or any combination of these diseases Recommended first-line therapies:  β-Blockers (except atenolol and β-blockers with intrinsic sympathomimetic activity)  ACE inhibitors (or ARBs)  Patients who remain hypertensive (BP > 130/80 mm Hg) despite treatment with a β-blocker, ACE inhibitor, or ARB, additional medications should be added to further reduce BP to target: Choice of agent is dependent on the presence of angina symptoms  Patients with uncontrolled HTN with angina  add a dihydropyridine CCB  Patients with SIHD whose angina symptoms are controlled  may consider adding dihydropyridine CCBs, thiazide diuretics, and/or mineralocorticoid receptor antagonists (MRAs) C. DM  Cardiovascular disease is the predominant cause of morbidity and mortality in patients with DM  Sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide 1 (GLP-1) receptor agonists  improve cardiovascular outcomes in patients with clinical ASCVD or at high risk for IHD GLP-1 receptor agonists (alone if intolerant to metformin or in combination with metformin)  Patients with DM in whom ASCVD predominates  cardiovascular benefit, independent of HgbA1c Substitute with an SGLT2 inhibitor (if not contraindicated)  if intolerant to GLP-1 receptor agonists or if GLP-1 receptor agonists cannot be used Combination of SGLT2 inhibitors and GLP-1 receptor agonists  if uncontrolled DM  SGLT2 inhibitors  empagliflozin and canagliflozin,  GLP-1 receptor agonists  liraglutide, semaglutide, and dulaglutide D. Antiplatelet agents  Platelets play a major role in the pathophysiology of ACS  Thromboxane A2 (TXA2) is a potent platelet activator 1. Aspirin: inhibits COX, an enzyme responsible for the production of TXA2, thereby inhibiting platelet activation and aggregation  In patients with IHD, aspirin reduces risk of MACE, particularly MI  Antiplatelet therapy with aspirin should be considered for all patients with SIHD, particularly in patients with a history of MI, in the absence of contraindications  Aspirin doses: 75-162 mg/d  in patients with or at risk for SIHD  Daily doses of aspirin > 162 mg  no additional benefit but increase bleeding risk 2. Consider clopidogrel  if aspirin is contraindicated (eg, aspirin allergy) or is not tolerated by the patient 3. DAPT (dual antiplatelet therapy): combination of P2Y12 receptor inhibitor [thienopyridine (clopidogrel, prasugrel) or ticagrelor] with aspirin to prevents platelet aggregation  Note: CYP2C19 and clopidogrel metabolism  PGs and CYP2C19 inhibitors Prasugrel and Ticagrelor  not dependent on CYP2C19  alternatives to clopidogrel When to consider dual antiplatelet in SIHD: in select patients with IHD  Following BMS implantation, patients with SIHD should be treated with DAPT for a minimum of 1 month compared to a minimum of 6 months following DES implantation  A longer period of DAPT is recommended in patients with SIHD treated with DES compared with BMS to prevent in-stent thrombosis  why ??---- Antiproliferative drugs in DES reduce the risk of in-stent restenosis but delay endothelialization Until endothelialization occurs, platelets are exposed to the foreign surface of the stent, thus stimulating platelet adhesion, activation, aggregation, and eventual thrombus formation within the implanted stent resulting in acute ischemia  A longer duration of DAPT (minimum of 12 months) is recommended for patients who have had stent implantation in the setting of ACS, regardless of the type of stent implanted (at least 1 year)  Patients with IHD who are eligible for “prolonged” or “extended” duration of DAPT [> 1 month in SIHD with BMS, > 6 months in SIHD with DES, > 12 months in ACS with either BMS or DES] are those who: A. Have not experienced a bleeding complication on DAPT B. Are not at high risk for bleeding (e.g, prior bleeding on DAPT, coagulopathy, oral anticoagulant use) Goal  to further reduce the risk of ischemic complications [late in- stent thrombosis and spontaneous MI, but at the expense of an increased risk of bleeding]  2. Relieve Acute Symptoms: Nitrates  Short-acting nitrates (nitroglycerin)  first-line treatment to terminate acute episodes of angina  Patients with SIHD should have sublingual nitroglycerin tablets or spray to relieve acute ischemic symptoms  All patients with SIHD should be prescribed sublingual nitroglycerin  Sublingual nitroglycerin tablets versus spray: Tablets are less expensive Spray is preferred for patients who have difficulty opening the tablet container or produce insufficient saliva for rapid dissolution of sublingual tablets  Isosorbide dinitrate: Has a longer half-life with antianginal effects lasting up to 2 hours. Available in sublingual form 2. Relieve Acute Symptoms: Nitrates MOA:  Nitrates undergo biotransformation to nitric oxide which activates smooth muscle guanylate cyclase, leading to increased intracellular concentrations of cGMP, release of calcium from the muscle cell, and ultimately, to smooth muscle relaxation  Resulting in venodilation, leading to reductions in preload  The resultant decrease in ventricular volume and wall tension leads to a reduction in myocardial oxygen demand  In higher doses, nitrates cause arterial dilation and reduce afterload and BP  Also, they increase myocardial oxygen supply by dilating the epicardial coronary arteries and collateral vessels, as well as relieving vasospasm  How to use:  At the onset of an angina attack, a 0.3 to 0.4 mg dose of nitroglycerin (tablet or spray) should be administered sublingually and repeated every 5 minutes up to three times or until symptoms resolve  Sublingual nitroglycerin may be used to prevent effort- or exertion-induced angina. In this case, the patient should use sublingual nitroglycerin 2 to 5 minutes prior to an activity known to cause angina, with the effects persisting for approximately 30 minute  The use of short-acting nitrates alone, without concomitant long-acting antianginal therapy, may be acceptable for patients who experience angina symptoms once every few days. However, for patients with more frequent attacks, other antianginal therapies are recommended  Important D/DI The use of nitrates within 24 to 48 hours of a phosphodiesterase type 5 inhibitor (eg, sildenafil, vardenafil, and tadalafil) is contraindicated Phosphodiesterase degrades cGMP, which is responsible for the vasodilatory effects of nitrates Concomitant use of nitrates and phosphodiesterase type 5 inhibitors enhances cGMP-mediated vasodilation and can result in serious hypotension, decreased coronary perfusion, and even death Points to emphasize when counseling a patient on sublingual nitroglycerin use include:   The seated position is generally preferred when using nitroglycerin because the drug may cause dizziness  Call 911 if symptoms are unimproved or worsen 5 minutes after the first dose  Keep nitroglycerin tablets in the original glass container and close the cap tightly after use  Nitroglycerin should not be stored in the same container as other medications because this may reduce nitroglycerin’s effectiveness  Repeated use of nitroglycerin is not harmful or addictive and does not result in any long-term side effects. Patients should not hesitate to use nitroglycerin whenever needed  Nitroglycerin should not be used within 24 hours of taking sildenafil or vardenafil or within 48 hours of taking tadalafil because of the potential for life-threatening hypotension 3. Pharmacotherapy to Prevent Recurrent Ischemic Symptoms  The overall goal of antianginal therapy is to allow patients with IHD to resume normal activities without symptoms of angina and to experience minimal to no adverse drug effects The drugs used to prevent ischemic symptoms are: 1. β-blockers 2. CCBs 3. Nitrates 4. Ranolazine They improve the balance between myocardial oxygen supply and demand They decrease the frequency of angina They delay the onset of angina during exercise  The overall goal of antianginal therapy is to allow patients with IHD to resume normal activities without symptoms of angina and to experience minimal to no adverse drug effects The drugs used to prevent ischemic symptoms are: 1. β-blockers 2. CCBs 3. Nitrates 4. Ranolazine No evidence that any of these agents prevent ACS or improve survival in patients with SIHD Combination therapy with two or three antianginal drugs is often needed Effects of antianginal medications:  They improve the balance between myocardial oxygen supply and demand  They decrease the frequency of angina  They delay the onset of angina during exercise 1. β-Blockers  Effect: Reduce HR, cardiac contractility, BP and ventricular wall tension  decrease myocardial oxygen demand Reduce heart rate  prolong diastole  increase coronary blood flow But they do not improve myocardial oxygen supply In the absence of contraindications, β-blockers are the preferred initial therapy to prevent symptoms of angina in patients with SIHD because of their potential cardioprotective effects (eg, after MI and/or in patients with HFrEF)  β-Blockers are contraindicated in patients with:  Severe bradycardia (heart rate < 50 beats/min)  Atrioventricular (AV) conduction defects in the absence of a pacemaker  β-Blockers should be used with caution in combination with other agents that depress AV conduction (e.g, digoxin, verapamil, and diltiazem)  increase the risk for bradycardia and heart block  Relative contraindications:  Asthma β1-selective blockers are preferred However, selectivity is dose dependent  β1-selective agents may  Bronchospastic disease induce bronchospasm in higher doses  Severe depression Precautions in patients with  DM  o Mask tachycardia and tremor (but not sweating) o Nonselective β-blockers  slow recovery from hypoglycemia in insulin- dependent diabetes  so selective drugs are used o B- blockers are not avoided in DM patients with SIHD particularly in patients with a history of MI who are at high risk for recurrent cardiovascular events  Heart failure o For Chronic HFrEF patients who are euvolemic  mortality benefit o Should be initiated in very low doses with slow uptitration to avoid worsening heart failure symptoms (due to –ve inotropic effects) Adverse effects: Fatigue Sleep disturbances Malaise Depression Sexual dysfunction Abrupt withdrawal  increase the frequency and severity of angina  the dose should be tapered over several days to weeks to avoid exacerbating angina 2. CCBs  Effects: Cause systemic vasodilation and reductions in afterload Reduce cardiac contractility Reduce myocardial oxygen Increase myocardial oxygen supply by dilating coronary arteries  Nondihydropyridine CCBs (verapamil and diltiazem)  more effective antianginal agents than the dihydropyridine CCBs CCBs are recommended as alternative treatment in SIHD when β-blockers are contraindicated or not tolerated CCBs may be used in combination with β-blockers when initial treatment is unsuccessful  Should be used with caution because both drugs decrease AV nodal conduction  increasing the risk for severe bradycardia or AV block  Long-acting dihydropyridine CCB is preferred  β-Blockers will prevent reflex increases in sympathetic tone and HR with the use of CCBs with potent vasodilatory effects For patients with variable and unpredictable occurrences of angina  indicate possible coronary vasospasm  CCBs are more effective than β-blockers in preventing angina episodes  Contraindications:  Verapamil and diltiazem  patients with bradycardia and preexisting conduction disease in the absence of a pacemaker  Avoided  In patients with HFrEF (except for amlodipine and felodipine that have less negative inotropic effects compared with other CCBs and appear to be safe in patients with left ventricular systolic dysfunction)  Use with caution in combination with other drugs that depress AV nodal conduction (eg, β-blockers and digoxin)  Short-acting agents in the management of SIHD  they may increase the risk of cardiovascular events 3. Long-Acting Nitrates  Produce effects within 30-60 minutes  Are equally effective at preventing the recurrence of angina when used appropriately  Drawback  tolerance with continuous use  may occur within the first 24 hours of continuous nitrate therapy  avoided by allowing daily nitrate -free interval of at least 8 to 12 hours  Nitrates do not provide protection from ischemia during the nitrate-free period  so nitrate-free interval should occur when the patient is least likely to experience angina (during the nighttime hours when the patient is sleeping, and myocardial oxygen demand is reduced  so dose long- acting nitrates so that the nitrate-free interval begins in the evening 3. Long-Acting Nitrates  Monotherapy for the prevention of ischemia should generally be avoided  Treatment with long-acting nitrates should be added to baseline therapy with either a β-blocker or CCB, or a combination of the two  Monotherapy with nitrates may be appropriate in patients who have low BP at baseline or who experience symptomatic hypotension with low doses of β-blockers or CCBs Adverse effects:  Postural hypotension: In patients with hypertrophic obstructive cardiomyopathy or severe aortic valve stenosis, may result in serious hypotension and syncope  contraindicated life-threatening hypotension may occur with concomitant use with phosphodiesterase type 5 inhibitors  should not be used within 24 hours of taking sildenafil or vardenafil, or within 48 hours of taking tadalafil  Dizziness, Flushing  Headache secondary to venodilation  resolves with continued therapy and may be treated with acetaminophen  Skin erythema and inflammation  with transdermal nitroglycerin minimized by rotating the application site 4. Renolazine  Anti-ischemic agent indicated for the management of chronic angina  Effects: Reduces angina and increases exercise capacity but does not reduce incidence of MACE Minimal effects on HR or BP  it may be an option in SIHD patients with low baseline BP or HR  Costly  so reserved for patients with angina refractory to other antianginal medications Adverse effects: Dizziness Constipation Headache Nausea Syncope QT interval prolongation: But, when used at recommended doses, the mean prolongation of QT interval is minimal (2.4 ms) Risk factors: hepatic impairment, concomitant medications known to interact with ranolazine or prolong QT interval  Contraindicated in patients with significant hepatic disease D/DI: Ranolazine is a CYP3A4 substrate, weak CYP2D6 substrate, CYP2D6 inhibitor, organic cation transporter 2 (OCT2) inhibitor, and both an inhibitor and substrate of P- glycoprotein (P-gp) Concomitant use with potent CYP3A4 inhibitors (eg, ketoconazole, clarithromycin, and nelfinavir) or inducers (eg, rifampin) is contraindicated Dose should be limited to 500 mg twice daily when combined with moderate CYP3A4 inhibitors including diltiazem and verapamil Should be used cautiously with P-gp inhibitors (eg, cyclosporine) and substrates (eg, digoxin) The maximum doses of simvastatin (20 mg daily) and metformin (1700 mg daily) are lower during concomitant treatment with ranolazine Pharmacotherapy with No Benef it or Potentially Harmful Effects 1. Hormone Replacement Therapy, Folic Acid, and Antioxidants 2. Herbal Supplements Ephedra containing products (eg, ma huang) Feverfew and garlic  may interact with antiplatelet and antithrombotic therapy and increase bleeding risk Dietary supplements purported to enhance sexual performance may contain phosphodiesterase-like chemicals  increase risk for serious hypotension with nitroglycerin. St. John’s wort  reduce the effectiveness of antianginal medications 3. COX-2 Inhibitors and NSAIDs  increase the risk for MI and stroke  The AHA recommends the use of COX-2 inhibitors be limited to low-dose, short-term therapy in patients for whom there is no appropriate alternative  Special Populations  Variant angina β-blockers should be avoided  worsen vasospasm due to unopposed α-adrenergic receptor stimulation CCBs (but short-acting CCBs should be avoided) and nitrates (immediate release nitroglycerin preferred treatments  Microvascular Angina Short-acting nitrates  treatment of choice for relieving acute symptoms ACE inhibitors and statins are beneficial β-blockers  first line to control symptoms of angina in patients with microvascular disease (more effective than CCBs and long-acting nitrates) Ranolazine  for patients with continued symptoms  Elderly Patients with IHD  Are more likely to have other comorbidities that may influence drug selection for the treatment of angina than younger patients  thus polypharmacy is more common in elderly patients  increasing the risk of D/DIs  thus, decreasing medication adherence  Are often more susceptible to adverse effects of antianginal therapies, particularly the negative chronotropic and inotropic effects of β-blockers and CCBs  thus, drugs should be initiated in low doses with close monitoring of elderly patients with IHD Duration of Therapy  Because these therapies reduce the risk for coronary events and death, treatment with antiplatelet (aspirin or clopidogrel), lipid-lowering, and neurohormonal-modifying medications for SIHD is generally lifelong  Antianginal therapy with a β-blocker, CCB, and/or nitrate is usually long term  A patient with severe symptoms managed with combination antianginal drugs who undergoes successful coronary revascularization may be able to reduce antianginal therapy. However, treatment with at least one agent is usually warranted OUTCOME EVALUATION: ASSESSING FOR DRUG EFFECTIVENESS AND SAFETY  Follow-up evaluations every 4 -12 months  Early in the treatment course (eg, first year), more frequent evaluations (every 4–6 months) are recommended  Length of the follow-up period may differ based on frequency and severity of symptoms, care coordination with other providers, regional practice patterns, patient preference, and physician availability  Monitor symptoms of angina at baseline and at each clinic visit to assess frequency and intensity of anginal symptoms and the effectiveness of antianginal therapy  Determining frequency of sublingual nitroglycerin use is helpful in making this assessment. If angina is occurring with increasing frequency or intensity, adjust antianginal therapy and refer the patient for additional diagnostic testing and possibly coronary intervention (eg, PCI or CABG surgery), if indicated.  Assess the patient for IHD-related complications, such as heart failure and arrhythmias  Routinely monitor hemodynamic parameters to assess drug tolerance  Assess BP at baseline, after drug initiation, and after dose titration. BP should be monitored periodically in patients treated with β-blockers, CCBs, nitrates, ACE inhibitors, and/or ARBs.  Routinely assess adherence to medical therapy and recommended lifestyle changes  Because of the potential for postural hypotension, warn patients that dizziness, presyncope, and even syncope may result from abrupt changes in body position during initiation or uptitration of drugs with α-blocking effects  Monitor heart rate in patients treated with drugs that have negative chronotropic effects (eg, β-blockers, verapamil, or diltiazem) or drugs that may cause reflex tachycardia (eg, nitrates or dihydropyridine CCBs). Treatment with β-blockers, verapamil, or diltiazem can usually be continued in patients with asymptomatic bradycardia. However, reduce or discontinue treatment with these agents in patients who develop symptomatic bradycardia or serious conduction abnormalities.  Regularly assess control of existing risk factors and the presence of new risk factors for SIHD. Modify the pharmacotherapy regimen to control these risk factors and lower the risk of IHD-related adverse events  Patients treated with ACE inhibitors and/or ARBs, routinely monitor renal function and potassium levels at baseline, after drug initiation and dose titration, and periodically thereafter. This is particularly important in patients with preexisting renal impairment or DM because they may be more susceptible to these adverse events ACUTE CORONARY SYNDROME U NSTABLE ANGI NA (U A) AND MYO CARDI AL I NFARCTI O N (MI ) Acute Coronary Syndromes  ACS encompasses all clinical syndromes compatible with acute myocardial ischemia and/or MI resulting from an imbalance between myocardial oxygen demand and supply  In contrast to stable angina, an ACS results primarily from diminished myocardial blood flow secondary to an occlusive or partially occlusive coronary artery thrombus  Caused by rupture of an atherosclerotic plaque [which occludes < 50% of lumen rather stable stenosis 70-90% in angina (SIHD)] --˃ platelet adherence, activation, aggregation, and the activation of the clotting cascade --˃ a thrombus composed of fibrin and platelets develops --˃ incomplete or complete occlusion of a coronary artery  Etiology: Endothelial dysfunction, inflammation, and formation of fatty streaks contribute to the formation of atherosclerotic coronary artery plaques, the underlying cause of CAD  Classification of ACS based on ECG changes 1. STE-ACS (STEMI; ST elevation ACS): Results from an injury that transects the entire thickness of the myocardial wall (complete occlusion) --˃ release of biomarkers, mainly troponins T or I, from the necrotic myocytes into the bloodstream 2. NSTE-ACS (non-ST elevation ACS): A. NSTEMI Limited to the subendocardial myocardium (partial occlusion) Smaller than a STE MI Results in lower mortality and complications B. Unstable Angina (UA): NSTEMI who do not develop infarction Ischemia is severe enough to result in the release of troponins Types of MI 1. MI type 1: occurs in coronary arteries where the stenosis occludes 20-30 minutes, Do not improve after 5 minutes of using sublingual nitroglycerin, or Worsen after 5 minutes of using sublingual nitroglycerin  Elderly, female patients, and patients with DM may present with a more atypical presentation, including epigastric pain, unexplained shortness of breath, or indigestion in the absence of chest pain which are often referred to as anginal equivalents Diagnosis of MI  Diagnosis of MI is confirmed when the following conditions are met in a clinical setting consistent with myocardial ischemia: Detection of a rise and/or fall of cardiac biomarkers with at least one value above the 99th percentile of the upper reference limit and with at least one of the following:  Symptoms of ischemia  ECG changes of new ischemia or development of pathological Q waves  Imaging evidence of new loss of viable myocardium  New regional wall motion abnormality  Identification of an intracoronary thrombus by angiography or autopsy Troponins  The most recent guidelines indicate that only the use of troponin assays is recommended to assess myocardial necrosis  Troponins are released into the bloodstream approximately 2-4 hours after an MI, and peak around 18-24 hours. Troponins can stay elevated for up to 2 weeks  A single measurement of non–high-sensitivity troponin is not adequate to exclude a diagnosis of MI, as up to 15% of values that were initially below the level of detection (a “negative” test) rise to the level of detection (a “positive” test) in subsequent hours  A single “positive” troponin may not be secondary to an MI as elevations can occur in other clinical conditions, such as pulmonary embolus, tachyarrhythmias, pericarditis, myocarditis, and sepsis, which can complicate diagnosis  Measurement of N-terminal pro B-type natriuretic peptide (BNP) may help predict long- term risk of mortality in patients with ACS but does not aid with acute diagnosis Treatment Treatment goals and strategy  Short term goal of treatment is to restore blood flow, prevent death, prevent re-occlusion, and relief discomfort  Long term is to control risk factor, prevent cardiac events, and improve quality of life A. Reperfusion Strategies for ACS 1. Patients with STEMI are at the highest short-term risk of death; therefore, immediate reperfusion strategies should be initiated. Early reperfusion therapy with primary PCI of the infarct artery within 90 minutes from the time of f ir st medical contact is the reperfusion treatment of choice for patients with STEMI who present within 12 hours of symptom onset The ACCF/AHA/SCAI PCI guidelines def ine a target time to initiate reperfusion treatment as ≤30 minutes of hospital arrival for f ibrinolytics (eg, alteplase, reteplase, and tenecteplase) and within 90 minutes from first medical contact for primary PCI For patients who present to a facility without PCI capability, it is recommended they be transferred to another hospital within 120 minutes of first medical contact for primary PCI Reperfusion Strategies for ACS  Fibrinolytic Therapy (Streptokinase, alteplase, Tenecteplase) Initiate ASAP (30 min) even before biomarkers reading Use when discomfort last for 20 min-24 hours with STE ≥ 1 mm or bundle block Avoid in patients with high risk of intracranial hemorrhage, bleeding, aortic dissection  use PCI  If patients with STEMI are not eligible for reperfusion therapy, additional pharmacotherapy should be initiated in the ED and the patient transferred to a coronary intensive care unit Reperfusion Strategies for ACS 2. Patient with NSTE-ACS: Risk-stratif ication is more complex because outcomes may vary between UA and NSTEMI  Various risk scores are available and should be used at presentation to predict the short-term and long-term event rates of patients presenting with NSTE-ACS [Thrombolysis in Myocardial Infarction (TIMI) risk score for NSTE-ACS, the Global Registry of Acute Coronary Events (GRACE) score, and the History, ECG, Age, Risk factors, and Troponin (HEART) score ]  There is a linear relationship between increasing scores and short-term risk (2–6 weeks) of adverse cardiac events including mortality, new or recurrent MI, or need for urgent revascularization Reperfusion Strategies for ACS 2. Patient with NSTE-ACS: Based on the risk assessment, a management strategy is chosen and patients are either treated using: (1) an early invasive strategy: Involves coronary angiography in patients classified as high- risk of CV events based on clinical characteristics (eg, high TIMI score 5–7).  Moderate- to high-risk patients are typically referred for an invasive strategy of early coronary angiography  Fibrinolytic therapy is not indicated and should not be used in patients with NSTE-ACS (2) an ischemia-guided strategy in which patients initially receive medication therapy only and will undergo an invasive evaluation if they fail medical therapy (eg, continued ischemia despite optimal medical treatment) or have objective evidence of ischemia on noninvasive stress testing. This strategy is reserved for patients stratified as low-risk (eg, TIMI score 0–3)  Patient symptoms, past medical history, ECG, and troponins are utilized to stratify patients into low, medium, or high risk of death, MI, or likelihood of failing pharmacotherapy and needing urgent coronary angiography and PCI Risk-stratif ication of the patie nt w ith NSTE-ACS is more com p le x b e ca u se outcomes may vary between UA and NSTEMI B. Early Pharmacologic Therapy for ACS All patients should receive within the first day of hospitalization, and preferably in the ED, are:  Intranasal oxygen (if oxygen saturation is low)  Symptoms relief: using sublingual (SL) nitroglycerin (NTG) Morphine to patients with refractory angina as an analgesic and a venodilator Intravenous (IV) NTG may be given in select patients with either acute HF, severe hypertension, or who are still experiencing pain despite SL NTG B. Early Pharmacologic Therapy for ACS  ASA  P2Y12 inhibitor (agent and timing of administration dependent on reperfusion strategy):All patients with ACS undergoing PCI should receive dual antiplatelet therapy (DAPT) with ASA and a P2Y12i antiplatelet (either clopidogrel, prasugrel, or ticagrelor) for at least 12 months following PCI regardless of stent type  Anticoagulation (agent dependent on reperfusion strategy)  Oral β-blockers should be initiated within the first day in patients without cardiogenic shock or other contraindications  ACE inhibitors (or ARB in ACE inhibitor-intolerant patients) should be initiated in select patients during hospitalization with ACS  High-intensity statin therapy should be initiated or continued during hospitalization in all patients without contraindications. Treatment of STEMI 1. Aspirin: give within 24 h for all pts without contraindication and indefinitely Start with 160-325 mg/day, and continue with 75-150 mg indefinitely (less GIT disturbances) 2. Thienopyridine (P2y inhibitors):Clopidogrel, prasugrel, ticagrelor, cangrelor iv Clopidogrel is administered as 300-600 mg loading dose prior to PCI followed by (75 mg) as maintenance dose Use with aspirin for all patients for at least 30 days-12 months following PCI May cause rash and GIT disturbances, bleeding and rarely thrombocytopenic purpura 3. Glycoprotein IIb/IIIa receptor inhibitors : eptifibatide or tirofiban In selected pts for only PCI undergoing patients taking unfractionated heparin (UFH) and not adequately treated by P2Yi May cause thrombocytopenia and bleeding Avoid with bivalirudin/fibrinolytics 4. Anticoagulants: infusion of unfractionated heparin (UFH), enoxeparin, bivalirudin In PCI undergoing patients and medical therapy Discontinue following PCI Optimize to reach aPTT May cause thrombocytopenia, thus low MWT heparin 5. Nitrates: venous and arterial dilatation, improve myocardial O2 demands and supply. Start Sublingual NG every 5 min until relief symptoms, use IV if persistent MI and up to 24 h after ischemia is relieved, control of HTN, or management of HF Do not use within 24 h of sildenafil and vardenafil or within 48 h tadalafil 6. B-blockers: Start with IV or oral ASAP (within 24 h) then continue oral indefinitely Caution with pulmonary congestion (use low dose to avoid shock), or decompensated HF 7. CCBs: Use only when B.B are contraindicated If patients with HTN and conventional coronary artery bypass (CCABs) use B.B instead Caution with AHF, if needed use amlodipine (no reflex tachycardia) not nifedipine 8. statin/insulin Initial pharmacotherapy for ST-segment elevation myocardial infarction (STEMI) a Options after coronary angiography also include medical management alone or coronary artery bypass graft surgery b Clopidogrel preferred P2Y12 when fibrinolytic therapy is utilized No loading dose recommended if age >75 years c Given for up to 48 hours or until revascularization d Given for the duration of hospitalization, up to 8 days or until revascularization dru e For use as adjunct therapy during PCI only are Administer ticagrelor at any time prior to or during the bar cangrelor infusion. Administer prasugrel or clopidogrel after the cangrelor infusion f If pretreated with UFH, stop UFH infusion for 30 minutes prior to administration of bivalirudin (bolus plus infusion) g In patients with STEMI receiving a fibrinolytic or who do not receive reperfusion therapy, administer clopidogrel for at least 14 days and ideally up to 1 year (ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; ASA, aspirin; CI, contraindication; FMC, first medical contact; GPI, glycoprotein IIb/IIIa inhibitor; IV, intravenous; MI, myocardial infarction; NTG, nitroglycerin; PCI, percutaneous coronary intervention; SC, subcutaneous; SL, sublingual; UFH, unfractionated heparin.) Pharmacotherapy for non–ST-segment elevation (NSTE) ACS Treatment is similar to STEACS, however, no fibrinolysis 1. Aspirin: 160-325 mg on day1, continue with 75-162 2. P2Y inhibitors: cangrelor IV, prasugrel, ticagroler, clopidogrel: start clopidogrel with loading dose (300-600 mg) then 75 mg Combination with aspirin when drug eluted stent Discontinue at least 5 days before CABG 3. Glycoprotein IIb/IIIa receptor inhibitors: Ttirofiban and eptifibatide not recommended to be used as medical therapy but only for high risk pts May use in selected pts undergoing PCI and pts with recurrent ischemia May cause bleeding esp with fibrinolysis, thrombocytopenia. Avoid with bivaliruden. 4. Anticoagulants: (unfractionated heparin, enoxeparin, bivaliruden, fondaparinux (not recommended)) continue for 48 h or until end of PCI or angiography LMWHs better than UFH 5. Nitrate: use sublingual then IV for 24 h 6. B.B/ CCBs/statin/insulin  aReasonable to choose ticagrelor over clopidogrel for maintenance P2Y12 for NSTE-ACS patients treated with an early invasive or ischemia-guided strategy bNot to be used as the sole anticoagulant during PCI Give additional UFH 85 units/kg IV without GPI and 60 units/kg IV with GPI cReasonable to choose prasugrel over clopidogrel for maintenance P2Y12 for NSTE-ACS patients undergoing PCI who are not at high risk for bleeding Do not use if prior history of stroke/transient ischemic attack (TIA), age >75 years, or body weight ≤to 60 kg (132 lb) dAdjunct agent to be used during PCI only Administer ticagrelor at any time prior to or during the cangrelor infusion Administer prasugrel or clopidogrel after the cangrelor infusion eMay require IV supplemental dose of enoxaparin fIf pretreated with UFH, stop UFH infusion for 30 minutes prior to administration of bivalirudin bolus plus infusion (ACE, angiotensin-converting enzyme; ACS, acute coronary syndrome; ARB, angiotensin receptor blocker; ASA, aspirin; CABG, coronary artery bypass graft; CI, contraindication; DES, drug-eluting stent; GPI, glycoprotein IIb/IIIa inhibitor; IV, intravenous; NTG, nitroglycerin; PCI, percutaneous coronary intervention; SC, subcutaneous; SL, sublingual; UFH, unfractionated heparin).  C. Prevention following MI  Aspirin: indefinitely, do not exceed dose of 81 mg/day  Clopidogrel: use for at least 12 months in NSTE, and 14 days-year in STE without PCI, but at least 12 months with PCI. Less bleeding if 3-6 months. Use low dose of aspirin when combination  Anticoagulation: warfarin in selected pts: chronic AF, LV thrombus, V wall abnormalities. But INR monitoring  B.B: start upon discharge when HF symptoms resolved and use indefinitely in low LVEF. 3 years if only ACS. If Contraindication use CCBs  ACEi/ARBS: In those with HT, DM, CKD, HF, reduced LVEF. use oral ACEis for all pts indefinitely especially for pts with LV dysfunction (