ischemic heart disease (ihd): angina pectoris angina pectoris is the collection of symptoms...
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Ischemic Heart Disease (IHD): Angina Pectoris
Angina pectoris is the collection of symptoms resulting from myocardial ischemia as a result of atherosclerosis of coronary arteries
IHD is also called coronary artery disease (CAD) or coronary heart disease (CHD)
CHD includes together with angina, acute coronary syndrome (ACS)
ACS comprises unstable angina (USA), acute myocardial infarction (MI), acute HF, and sudden death
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Features of Angina Pain
Location: Over the sternum or near to it, Small area of chest (≤3 cm), entire right/left side, leg pain
Radiation to left shoulder/arm, jaw, tongue, teeth Duration: Ranges from seconds to hours Descriptors: Sharp, sticking, stabbing, knifelike,
pricking, gas Triggers: Exercise, heavy meals, body position,
cold weather Nitroglycerin relief: after 45 seconds-5 min ECG: ST-depression, T-wave inversion 2
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Causes of Angina Pectoris
Typical angina results from advanced coronary atherosclerosis in at least one moderately sized epicardial coronary artery
In general, obstructions in diameter of 60% or greater are likely to be associated with angina, whereas lesions of less than 50% ordinarily do not cause ischemia
Severe angina (chest pain caused by little exertion) is usually associated with coronary obstructions of 80% to 100%
Patients are often characterized as having one-, two-, or three-vessel disease, as determined by coronary arteriography
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Causes of Angina Pectoris
A, Several high-grade narrowing of a right coronary artery. B, Severe (>90%) stenosis (arrows) of a left anterior descending coronary artery
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Coronary Stenosis Coronary artery obstructions are capable of changing
caliber, Constriction or narrowing of a preexisting lesion can be a
factor in precipitating angina and myocardial ischemia
Eccentric
Concentric
Nitrates
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Risk Factors for Coronary Artey Disease
Modifiable CAD Risk Factors Non-modifiable CAD Risk Factors Causative Risk Factors (directly associated with CAD development)
o Cigarette smoking o Hypertension o Kidney disease o Diabetes mellitus (Type-1 & 2) o Elevated LDL & Reduced HDL
Predisposing Risk factors (Direct Impact on Causative RF Development)
Obesity (BMI? 25 kg/m2) Age: Males > 45 years Females > 55 years
Physical inactivity Male Gender Socioeconomic factors Family history of coronary artery disease
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Non-standard CAD Risk Factor
Non-standard CAD Risk Factor Significance Lipoprotein(a) Lp(a) is a cholesterol-rich
plasma lipoprotein with a structure very similar to low density lipoprotein
Increased levels of Lp(a) are associated with high risk for atherothrombotic cardiovascular disease.
Homocysteine Homocysteine is sulphur containing amino acid and is derived from dietary methionine.
Hyperhomocysteinemia is a risk factor for development of cardiovascular disease.
It is associated with other cardiovascular risk factors like male gender, old age, smoking, high blood pressure, elevated cholesterol and lack of exercise.
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AHA/ACC Guidelines for the Secondary Prevention for Patients with Coronary and
Other Atherosclerotic Vascular DiseaseRisk Factor Intervention & Goal
Smoking Complete cessation
Blood Pressure <140/90 mm Hg & <130/80 mm Hg in diabetics & kidney disease
Lipid Metabolism LDL-C <100 mg/dL, If triglycerides >200 mg/dL, non–HDL-C should be <130 mg/dL
Diabetes Hemoglobin A1C <7%
Physical activity At least 30 min of moderate intensity aerobic activity (e.g., brisk walking) for minimum of 5 days/wk
Body Weight BMI between 18.5–24.9 kg/m2
Waist circumference men <40 in, women <35 in
Influenza vaccination
Patients with CAD should have an annual influenza vaccination
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Myocardial Oxygen Supply & Demand
Oxygen Demand
Oxygen Supply
•Coronary Blood Flow•Oxygen Extraction & Saturation
•Cardiac Contractility/Rate•Ventricular Wall Tension (Systolic & Diastolic)
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Treatment Overview Medical management should be individualized Risk factor modification is indispensible for
prevention & treatment of CHD Goal of therapy: reduction of the number, severity,
& duration of anginal attacks Six drug classes are used alone/ in combinations:o Nitrateso β-blockerso Calcium channel blockerso Antiplatelets, Anticoagulantso ACE inhibitors
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Diagnostic Procedures
Exercise tolerance test: ECG signs of ischemia, angina
• HR-SBP product is usually used Myocardial imaging, echocardiographic or
nuclear, preferred to exercise tolerance• Pharmacologic stress (e.g, dobutamine or
adenosine injection) can be used Cardiac catheterization & subsequent
angiography can detect coronary artery spasm
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Anti-Ischemic Drug TherapyNITRATES
Treatment of all anginal syndromes Mechanism & Properties: Inhibition of thromboxane synthase Venodilation is more than arterial because the latter
needs higher plasma nitrate level NO production→ + vascular SM –SH groups → S-
nitrothiols → Activation of Guanylate cyclase → Increased intracellular cGMP
Venous dilation →lowered preload →reduction of ventricular filling pressure →decreased myocardial O2 consumption → anginal pain relief
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NITRATES
Coronary artery vasodilation → increased coronary blood flow increased oxygen supply
Angiographic studies showed that coronary arteries with eccentric atherosclelerotic lesion will dilate in response to nitrates
Another antianginal agent (ß-blocker or CCB) must provide the antianginal effect during the nitrate-free period
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Short-Acting NitratesSublingual Nitroglycerin (NTG)
Dose: mostly 0.4 mg, relief of pain, objective hemodynamic effect (10 mm Hg drop, ↑HR)
Onset: 1-3 min, duration:10-30 Prevention of attack: To be taken 5-10 min before the
exertion that possibly precipitate angina Instructions to Patient:o Sit immediately, place NTG tablet under tongueo Max three tablets over 15 mino If pain persists >30 min →suspected MIo NTG tablets are volatile →a tablet left outside loses activity
in mino An open bottle →use for 6-12 months 14
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Nitroglycerin Lingual Spray
NTG lingual spray, 0.4 mg/metered dose is an alternative for SL NTG
Each canister has 200 metered dose/3 years shelf-life
Spray a single dose under or onto the tongue NTG lingual spray should not be inhaled Max dose: three sprays over 15 min
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Long-Acting Nitrates
o NTG: SR capsule, Topical ointment, transdermal patches
o Isosorbide Dinitrate (ISDN): oral, SR, SL, and chewable
o Isosorbide Mononitrate (ISMN): SR tab, rapid-release tablets
Long-acting nitrates are the prevention corner stone therapy of all types angina
CCB can be an alternative especially if angina patient has improperly controlled HTN
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Side Effects to Nitrates
Hypotension Headache: tolerance develops after few weeks Dizziness Syncope/fainting necessitates dosage reductiono Severe hypotension & bradycardia caused cardiac
arrest in patients experiencing MIo NTG-induced vaso-vagal response → NTG
syncope → leg elevation, atropine, fluids Met-Hbemia is important when large IV NTG
doses used 17
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Nitrate Tolerance
Tolerance is unlikely to occur with NTG (SL, oral spray), and SL isosorbide dinitrate
Tolerance is likely with long-acting oral nitrates (ISMN) & transdermal patches
12 hour NTG transdermal patches’ intermittent therapy minimize tolerance
Intravenous NTG used in unstable angina (USA) & severe HF is associated with tolerance
12 hour intermittent intravenous NTG limit nitrate tolerance
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Nitrate Tolerance Minimization
Nitrate-free interval of 10-12 hours minimize tolerance to therapeutic activity
Lowest effective nitrate dose lower tolerance
ß-blocker or CCB is given to provide anginal protection during nitrate-free period
Long-acting nitrates have no evidence of causing tolerance to SL nitrates’ use
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MECHANISM OF Nitrate Tolerance
Depletion of vascular –SH groups, plasma volume expansion, neurohormonal activation
Nitrates increases superoxide anion (O2-) + NO →
peroxynitrite producing:• Decreased endothelial NO production• Increased sympathetic & RAA systems• Increased vasoconstrictor responsiveness• Peroxynitrite-dependent assumption stimulates the
question: dose nitrate have long-term detrimental effects?
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ISOSORBIDE DINITRATE & MONONITRATE (ISDN & ISMN)
ISDN oral formulation is used usually three times a day especially in severe angina
Usually ISDN is taken at 7 AM, Noon & 5 PM to allow 12 hr nitrate-free period
ISDN can be given twice/day in moderate severity angina
Isosorbide mononitrate (ISMN) can be given once or twice/day (early morning & 7 hrs later)
ISMN has better patient compliance
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ß-ADRENERGIC BLOCKERS
Decreased myocardial oxygen consumption by lowering adrenergic-related HR, BP & contractility
ß2-adrenergic receptors were shown to be present in the heart by 10-40%, possibly augment cardiac contractility & HR
In chronic angina: ß-blockers should be given before nitrates & CCBs
ß-blockers are more effective than the other two agents in lowering incidence of anginal episodes
The three classes are similar in mortality reduction They lower CV morbidity/mortality in HTN, HF, or
MI patients 22
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ß-ADRENERGIC BLOCKERS THERAPEUTIC ENDPOINT
Anginal attacks frequency & NTG consumption are indices for therapeutic efficiency of antianginals
Reduction in resting HR is best monitored to adjust ß-blockers’ dose
Dose can be increased till HR is 55 b/min, even 50 b/min is acceptable for asymptomatic patients
ß-blockers with ISA do not lower resting HR Exercise testing is the best, though least practical: Reduction of exercise ST-depression HR-SBP product usually decreases (lowered wall
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β-Adrenergic Blockers Dosing
β-blocker pharmacodynamic actions are longer than their plasma half-lives
Usually taken once to twice daily for angina Atenolol t1/2 is 10 hours but clinical evidence
support the effectiveness of once daily regimen Propranolol is of short 2-3 hrs t1/2, yet its BP/HR
lowering effects are pronounced for 12 hours Clinical evidence support the effectiveness of
twice daily regimen of propranolol
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β-Adrenergic BlockersCardio-selective & Contraindications
Cardio-selective ß-blockers did NOT produce adverse respiratory effects in moderate respiratory diseases (Meta-analysis)
Cardio-selective ß-blockers low inhibition of ß2-induced peripheral vasodilation (α-vasoconstrictn)
• Atenolol/acebutalol/metoprolol preferred in peripheral vascular disease & Raynaude’s disease
DIABETES is NOT a contraindication for ß-blockers• Lower mortality in diabetics after MI• CAD is more severe in diabetics & has worse
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β-Adrenergic Blockers
ISA ß-blockers→less effect on lipid/glucose ISA ß-blockers→ less bradycardia →less effective
in angina or worsen angina (better avoided) ß-blockers abrupt withdrawal can be serious in
severe atherosclerosis/USA →severe CV effects like acute MI & sudden cardiac death
ß-blockers withdrawal schedule can be a two-weeks four-steps on 2-3 days schedule
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CALCIUM CHANNEL BLOCKERS
Amlodipine & felodipine (DHPs) are the only CCBs that can be used in HF patients
Nifedipine IR, diltiazem & verapamil should be avoided in HF patients
INDICATIONS: Vasospastic & classical exertional angina
CCBs by arterial dilation →decrease myocardial O2 demand
CCBs cause coronary dilation Coronary → increase myocardial O2 supply
Vasospasm can occur at atherosclerotic site, CCB can cause dilation
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CALCIUM CHANNEL BLOCKERS
NIFEDIPINE: 10% nifedipine patients experience angina worsening because of powerful dilation→ reflex increase in HR → increase O2 demand → can cause acute MI
This is frequent with IR preparations IR nifedipine no longer used for any disease SR nifedipine is used Side Effects: hypotension, dizziness (15%), facial
flushing & headache & nausea Peripheral edema with DHPs Constipation with verapamil
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CALCIUM CHANNEL BLOCKERS
contraindications Severe hypotension Severe aortic stenosis Extreme bradycardia Moderate to severe HF Cardiogenic shock Sick sinus syndrome Second/third degree A-V block
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COMBINATION THERAPY
ß-blockers-nitrate-CCB triple therapy is an option to maximize benefit & lower side effects
Disadvantages: Cost, possible additive side effects (HF worsening by ß-blocker-CCB)
Excessive vasodilation-bradycardia in triple therapy can be minimized using CCB with less potent vasodilating properties
Initial therapy in chronic angina: ß-blocker Then Nitrate or CCB is added according to patient
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COMBINATION THERAPY
Nitrates, as a second class, are preferred in patients with LV dysfunction
CCBs, as a second class, are preferred whenever further BP control is needed
Two CCBs combination: Nifedipine with verapamil or diltiazem lower dizziness & effects on cardiac conduction & contractility
Two CCBs combination used when standard triple therapy (at max tolerable individual doses) is still ineffective
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Ranolazine (FDA Approval 2006)Mechanism of Action
Unlike traditional antianginal agents, it does not have any appreciable effects on heart rate, arterial resistance vessels, the myocardial inotropicity, or coronary blood flow
It does NOT affect blood pressure or heart rate Ranolazine does not affect myocardial oxygen supply
or demand Early preclinical work showed that it inhibits fatty acid
oxidation, however, at higher plasma level than those used therapeutically
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Ranolazine (FDA Approval 2006)Mechanism of Action
It is now known that ranolazine's anti-ischemic effects are modulated through inhibition of the late sodium current (INa)
By inhibiting late sodium entry, and hence calcium overload during ischemia
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Ranolazine (FDA Approval 2006)Mechanism of Action
Ranolazine effectively inhibits the consequences of ischemia as decreased microvascular perfusion, as well as increased myocardial oxygen demand
This novel mechanism of action offers the possibility of complementary effects when added to more traditional antianginal agents which act through their hemodynamic actions
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Vasculoprotective Drug Therapy
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Rationale for CONVERTING ANGIOTENSIN ENZYME INHIBITORS
ACEIs reduced MI by 23% in HF patients → Are ACEIs beneficial in LV dysfunction-free CAD patients and post-acute MI patients?
The HOPE study: 9,297 patients with chronic CAD and no HF Ramipril reduced incidence of death, MI, stroke,
need for revascularization, and angina worsening Benefit was independent of BP lowering effect Patients were on standard angina therapy
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CONVERTING ANGIOTENSIN ENZYME INHIBITORS
EUROPA study: 12,218 PATIENTS, 4.2 YEARSo Perindopril in stable angina with no HFo Reduction of combined incidence CV death, MI &
cardiac arrest o Similar to HOPE study, is this beneficial effect
class-related?o Tissue binding & inhibition of ACE in myocardium
& endothelium varies among different ACEIs
For ARBs, there is no clinical trials yet
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Antiplatelet TherapyAspirin
Platelet activation produces coronary occlusion either by formation of a platelet plug or through release of vasoactive compounds from the platelets
A single 100-mg aspirin dose virtually eliminates thromboxane A2 production, whereas doses below 100 mg result in a dose-dependent reduction in thromboxane A2 synthesis
Determine the effect of aspirin doses on the TXA2 to PGI2
Selective inhibition of platelet-generated TXA2 synthesis has been shown with 75 mg of controlled-release aspirin daily
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Aspirin
It has been believed that higher doses of aspirin would produce a higher level of efficacy than low doses
However, all available literature indicates that low dosages of aspirin (75–325 mg/day) are as effective as higher dosages (625–1,300 mg/day) in the treatment of angina
Therefore, current guidelines recommend a daily dosage of 75 to 162 mg orally for the prevention of MI and death in patients with CAD
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Clopidogrel
Clopidogrel (Plavix), a thienopydridine, inhibits platelet function in vivo via noncompetitive antagonist of the platelet ADP receptor
Clopidogrel at a dosage of 75 mg orally every day was demonstrated in one study to be slightly more effective than aspirin in the secondary prevention of MI and death in patients with various manifestations of atherosclerotic vascular disease
Clopidogrel historically was to serve as an alternative antiplatelet agent in patients with a true contraindication to aspirin
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Clopidogrel
The magnitude of difference in benefit seen with clopidogrel was quite small and not sufficient to justify its broad scale use in the treatment of CAD
Based on this study, the role of clopidogrel historically was to serve as an alternative antiplatelet agent in patients with a true contraindication to aspirin
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Aspirin/Clopidogrel Combination
The combination of aspirin and clopidogrel was compared with aspirin alone in patients with acute coronary syndromes withoutwithout ST-segment elevation in the CURE study for an average of 9 months9 months
The combination of aspirin and clopidogrel significantly reduced CVS death, nonfatal MI, or stroke
The results of the CURE study were confirmed in the Clopidogrel for Results of Events During Observation (CREDO) trial where patients with ACSACS who were treated with percutaneous coronary stent intervention received aspirin/clopidogrel for 1 year
Patients receiving both aspirin and clopidogrel for 1 year had a lower incidence of death, MI, and stroke in comparison to patients who only received aspirin
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Aspirin/Clopidogrel Combination in Chronic CAD
Given the beneficial effects seen in patients with recent ACS, and in patients with PCI plus stent placement
Is dual therapy with aspirin plus clopidogrel would be superior to aspirin in the treatment of chronic stable CAD
In the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial, 15,063 patients with documented vascular disease (CAD, cerebrovascular, peripheral arterial disease), or no documented vascular disease but with multiple cardiovascular risk factors, were assigned to aspirin alone or aspirin plus clopidogrel for an average of 28 months duration
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Aspirin/Clopidogrel Combination in Chronic CAD
Unlike the results from ACS studies, however, the combination of aspirin plus clopidogrel did NOTreduce the incidence of the primary endpoint (risk of death, MI, stroke, or coronary revascularization) as compared with aspirin alone
In a secondary analysis of patients who entered the trial with documented vascular disease, dual therapy did produce statistically significant reductions in the primary endpoint as compared with aspirin
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VARIANT ANGINA (CORONARY ARTERY
SPASM) ST-segment elevation is the cardinal mark for
variant angina It results from severe large coronary artery
segmental spasm with transient total occlusion Transient arrhythmias & conduction disturbances
may be observed during pain or no symptoms ↑ HR-SBP product characterizing stable angina
during pain does not occur with variant angina Angiography can show the vasospasm Ergonovine test can provoke the unpredictable
coronry vasospasm by stimulating α-adrenergic & 5-HT receptors 45
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VARIANT ANGINA therapy
CCBs are usually preferred over nitrates or ß-blockers
All CCBs are equally effective but intrinsically long-acting or SR forms are preferred
CCB-Nitrate combination should be tried when max CCB dose is still ineffective
Aspirin is indicated for variant angina ß-blockers mostly worsen variant angina by
unmasking α-vasoconstriction by ß2-blockade
Cardioselective ß-blockers can worsen variant angina
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VARIANT ANGINA therapyPrognosis
50% of variant angina patients undergo full spontaneous recovery via unknown mechanism
This occurs with isolated vasospasm without atherosclerosis (short-duration symptoms)
Therapy can be stopped, after gradual tapering, if patients are free from pain, significant arrhythmias, or silent ischemic episodes for one year
Risk factor modification may enhance variant angina remission
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VARIANT ANGINA therapyDevelopment of mi
Variant angina can proceed to MI or myocardial death especially in multi-vessel coronary spasm
In a small group of hospitalized variant angina patients, 76% experienced morbid cardiac events (acute MI, sudden death, & CA bypass graft) within a month of angina onset
Aggressive CCB+NTG infusion during the early stages improve prognosis
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Acute Coronary syndrome (ACS)
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UA/NSTEMI Goal of Therapy
Prevent total occlusion of the infarct-related artery
(a) Glycoprotein (GP) IIb/IIIa inhibitors, other antiplatelet agents, and anticoagulants
(b) Percutaneous coronary intervention (PCI) can be either or both:
(1) Percutaneous transluminal coronary angioplasty, (i.e., “balloon”)
(2) Stent implantation
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Unstable Angina Initial Treatment
“MONA” (Morphine, Oxygen, NTG) Hospitalization, bed rest, & treatment of underlying
predisposing factors (HTN, infection, HF, arrhythmias) are indispensable
Pharmacologic strategy aims to reduce ischemia & inhibit thrombotic process
ß-blockers must be acutely administered to prevent the progression to MI & death initialy by IV route, then orally
Nitrates both SL & then intravenously for pain relief & ischemia reduction
CCBs can reduce ischemia bur should be reserved to ß-blockers resistant patients 52
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Unstable Angina TreatmentAntiplatelets
Chewable aspirin (325 mg dose) should be administered to all patients as they prevented progression to MI & death
Aspirin (81-325 mg/day) & clopidogrel (300 mg load, 75 mg PO) combination acutely & up to 1 year has been shown to decrease risk of CV death, MI & stroke in USA/NSTEMI patients
Patients with USA/NSTEMI receiving aspirin & undergoing PCI, PCI, clopidogrel should be given prior to the procedure followed by 1-12 months treatment
Patients undergoing CABG, clopidogrel should be discontinued for 5-7 days before procedure
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Unstable Angina Treatment
Antithrombin: UFH & LMWHs were found to be equivalent as regards improving clinical outcomes in USA/NSTEMI patients
• Enoxaparin, recommended by ACC/AHA, shown to be superior to UFH in preventing CV events
GP IIb/IIa receptor antagonists, in addition to aspirin & UFH/LMWH, decreased composite risk death, MI, urgent revascularization in patients USA/NSTEMI: Eptifibatide and tirofiban
Abciximab is NOT approved for UA/NSTEMI medical management unless PCI is planned within 24 hrs
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Revascularization: Percutaneous Coronary Intervention
Percutaneous coronary intervention (PCI), also known as angioplasty, involves the percutaneous insertion of a balloon catheter into the femoral artery in a similar fashion to angiography
Stents can be of the bare metal (BMS) variety, or contain a drug impregnated on the surface of the stent to prevent re-stenosis (drug-eluting stent or DES)
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Revascularization: Percutaneous Coronary Intervention
Mechanical disruption of the atherosclerotic plaques and exposure of plaque contents to the bloodstream during PCI, can cause acute thrombotic events likee MI & death
Potent antiplatelet and antithrombotic strategies are needed to prevent such reactions
Initially, strategies involved the use of high-dose unfractionated heparin and aspirin
Current strategies involve the administration of aspirin, clopidogrel, an antithrombin agent, as well as a glycoprotein (Gp) IIb/IIIa receptor antagonist in selected patients
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Antiplatelets in Revascularization
In patients who are NOT on daily aspirin, 325 mg aspirin should be initiated 2 hrs before procrdure
A 600 mg clopidogrel loading dose on or before the procedure is recommended, producing antiplatelet action within 2 hours
GPIIb/IIIa receptor antagonists improve outcomes in patients undergoing PCI as well as UA/NSTEMI patients medical management
These agents, when administered IV during PCI and for 12 to 24 hours afterward, significantly decrease the risk of death, acute MI, or need for repeat PCI
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Indications and Dosing of Glycoprotein IIb/IIIc Receptor Antagonists
Indication Abciximab Eptifibatide Tirofiban
Percutaneous transluminal coronary angioplasty (PCTA)
0.25 mg/kg IV bolus, then 0.125 mcg/kg/min IV infusion × 12 hr
180 mcg/kg IV bolus, then 2.0 mcg/kg/min IV × 20–24 hrRepeat 180 mcg/kg IV bolus 10 mins after first bolus
Not approved use
Coronary stent placement
0.25 mg/kg IV bolus, then 0.125 mcg/kg/min IV infusion×12 hr
Same as above Not approved use
Acute coronary syndrome (unstable angina and non–STEMI)
Not approved use
180 mcg/kg IV bolus, then 2.0 mcg/kg/min IV × 20–24 hr
0.4 mcg/kg/min IV load × 30 mins, then 0.1 mcg/kg/min IV infusion × 48–102 hr
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Use of GpIIb/IIIa Antagonists in UA/NSTEMI
The Gp IIb/IIIa receptor antagonists currently are recommended as options in patients with USA/NSTEMI in one of the following groups:
in whom catheterization and PCI is planned who have continuing ischemia despite treatment
with aspirin, UFH/ LMWH/ fondaparinux/ bivalirudin, nitrates, β-blockers, and clopidogrel
Patients have other high risk features, such as elevated troponin or ST-segment changes on the initial ECG
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Antithrombin Therapy & Revascularization
Unfractionated heparin (UFH), LMWH enoxaparin and the direct thrombin inhibitir bivalirudin are options for administration at the time of the procedure
They are discontinued after PCI procedure unless a compelling indication exists
They are used in the following: ACS: Medical management PCI: Therapy initiated at time of procedure PCI: Continuation of prior therapy
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