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

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

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

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

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

tension & HR) 23

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

prognosis over that developed in non-diabbetics 25

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

status (No fixed guidelines)30

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

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

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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