Recent advances in the management of chronic stable angina II. Anti-ischemic therapy, options for refractory angina, risk factor reduction, and revascularization

Figures & data

Table 1 Common forms of nitrates used as anti-ischemic agents in angina

Compound	Route	Usual dose (daily unless mentioned)	Onset of action, min	Duration
Nitroglycerin	Sublingual	0.3–0.6 mg up to 1.5 mg as needed, up to 3 tabs	2–5	10–30 min
	Spray/mist/aerosol	0.4 mg, 1–2 sprays prn as needed, up to 3 doses 5 min apart	2–5	10–30 min
	Ointment 2%	7.5–40 mg, 6 × 6 in or 15 × 15 cm	20–60	3–8 h
	Transdermal patch	0.2–0.8 mg/h q24 h; remove at night for 12 h	>60	8–12 ha
	Intravenous	5–200 μg/min (used in ACS) titrated to symptom relief, headache, or hypotension	1–2	While infusingb
Isosorbide dinitrate	Oralc	5–80 mg, 2–3 times daily	30–60	4–6 h
Isosorbide mononitrate	Oral	20 mg twice daily, 7–8 h apart	30–60	6–8 h
Isosorbide mononitrate SR	Oral	30–240 mg daily, given once daily	30–60	12–18 h

a Requires 8–10 h nitroglycerin free recovery period because of tolerance;

b May exhibit tolerance in 7–8 h;

c Also available in sublingual form.

Abbreviations: q24 h, every 24 hours; ACS, acute coronary syndrome; SR, sustained release.

Table 2 β-Adrenergic blockers used to treat angina

Druga	Selectivity	Dose time to peak action after oral intake, h	Elimination half-life, h	Dose
Atenolol	β1	2–4	6–9	50–200 mg/d
Bisoprolol	β1	2–4	9–12	10 mg/d
Esmolol, IV	β1	2–5 min	9 min	50–300 μg/kg/min
Metoprolold,e	β1	1–2	3–6	50–200 mg twice daily
Propranolold	None	1–2	3–5	80–120 mg twice daily
Nadolol	None	3–4	14–24	40–80 mg/d
Timolol	None	1–2	4–5	10 mg twice daily
Carvedilolc,d	None	1.0–1.5	7–10	3.125–25 mg twice daily
Labetalolb	None	2–4	3–6	200–600 mg twice daily

a Drugs with partial agonist activity are not included;

b Combined α-blocking and β-blocking activities;

c Combined α-blocking, β₁-blocking, and β₂-blocking activities;

d Antiarrhythmic class I effect;

e An extended release formulation may be begun at 100 mg daily.

Abbreviation: IV, intravenous.

Table 3 CCBs are classified chemically, which reflects their properties

Type	Properties	Examples
Dihydropyridines (DHP)	Peripheral and coronary vasodilators, negative inotropic action	Amlodipine, nifedipine, felodipine, isradipine, nicardipine, nisoldipine
Nonhydropyridines (non-DHP)
Phenylalkylamine	Additional negative chronotropic and inotropic actions	Verapamil
Benzothiazepine	Additional negative chronotropic and inotropic actions	Diltiazem
Mixed sodium and CCB	Nonselective, blocking delayed rectifier K^+ current and fast Na^+ current. Also inhomogeneous electrical effects, prolonged QT interval, and linked to torsade de pointes. Not in current use	Bepridil
Antihistamine	Used for migraine prophylaxis, PAD, vertigo, but not for angina.	Flunarizine

Abbreviations: CCBs, calcium channel blockers; PAD, peripheral vascular disease.

Table 4 CCBs used for ischemic heart disease

Drug	Duration of action	Usual dose	Common side effects
Dihydropyridines (DHP)
Nifedipine, slow release	Long	30–180 mg/d	Hypotension, edema, dizziness, flushing, nausea, constipation
Amlodipine	Longa	5–20 mg qd	Headache, edema
Felodipine, SR	Long	5–10 mg qd	Headache, edema
Isradipine, SR	Medium	2.5–10 mg bid	Headache, fatigue
Nicardipine	Short	20–40 mg tid	Headache, edema, dizziness, flushing
Nonhydropyridines (non-DHP)
Diltiazem, immediate release	Short	30–80 mg qid	Hypotension, dizziness, flushing, bradycardia, edema
Diltiazem, slow release	Long	120–320 qd	Hypotension, dizziness, flushing, bradycardia, edema
Verapamil, immediate release	Short	80–160 mg tid	Hypotension, negative inotropism, HF, bradycardia, edema
Verapamil, slow release	Long	120–480 mg qd	Hypotension, negative inotropism, heart failure, bradycardia, edema

a Has the longest half life of the CCBs of 35–50 h.

Abbreviations: CCBs, calcium channel blockers; SR, sustained release; tid, 3 times a day; qid, 4 times a day; qd, daily; HF, heart failure.

Table 5 Cardiovascular effects of nitrates, CCBs, and β-blockers in angina

Variable	Nitrates	Calcium channel blockers	β-blockers
Collateral blood flow	↑↑	↑↑	→
Endomyocardial to epimyocardial flow	↑↑	↑	↑
Heart rate	↑ (reflex)	↑↓ (reflex)	↓↓
Left ventricular wall tension	↓↓	↓	↑→
Myocardial contractility	↑ (reflex)	↑ ↓→ (reflex)	↓↓
Cardiac work	↓↓	↓↓	↓↓

Abbreviation: CCBs, calcium channel blockers.

Table 7 Selected recommendations from the ACC/AHA updated guidelines on risk reduction in patients with angina

Risk factor	Recommendations	COR/LOEa	Comments (not part of the guidelines)
Smoking	Smoking must be stopped immediately, and second-hand smoke should be avoided. Pharmacotherapy with nicotine and other approved agents should be used along with referral to special programs. Use a stepwise strategy: Ask, Advise, Assess, Assist, and Arrange.	I (B)	Smoking is a potent and pernicious risk factor. Cessation may lower risk by 60% in 3 y, with half of that manifested within the first 3–6 months.
Hypertension	BP should be kept <140/90 mmHg, or <130/90 mmHg in DM or CKD.	I (A)	Evidence at the ACC 2010 sessions raised doubts about the wisdom of tight BP control in DM.^Citation205,Citation206
	Lifestyle modifications: weight control, physical activity, low alcohol, sodium intake, high consumption of fresh fruits and vegetables and low-fat dairy products – an improved “DASH diet” is advised.	I (B)	New Joint National Conference 8 Guidelines for hypertension are expected late in 2011.
	For patients with established CHD, use β blockers or ACE inhibitors first, then other agents.	I (C)	When a prior AMI has not occurred, ACE/ARB use is quite discretionary – see below.
Dyslipidemia	When baseline LDL ≥ 100 mg/dL, begin drugs with lifestyle measures.	I (A)	Intensify therapy to reach 30%–40% reduction in high-risk patients, or <70 mg/dL.
	Daily exercise, weight control, low-saturated fat diet <7%, reduce dietary TFA, and cholesterol intake <200 mg/d.	I (B)	The less dietary TFA, the better.
	If TG = 200–499 mg/dL, non-HDL should be <130 mg/dL.
	Add plant stanols 2 g/d and/or soluble fiber >10 g/d.	IIa (A)	A somewhat greater intake may improve results, with maximum reduction of about 9% from each maneuver.
	Lowering LDL < 70 mg/dL or using high-dose statins is reasonable.	IIa (A)	Aggressive LDL lowering is being favored in many different clinical situations, but still leaves unacceptable residual risk.
	If baseline LDL is 70–100 mg/dL, lowering LDL to < 70 mg/dL is reasonable.	IIa (B)
	When TG are 200–499 mg/dL, lowering non-HDL < 100 mg/dL is reasonable.	IIa (B)	Although LDL remains the official primary target, non-HDL better incorporates the atherogenicity of other particles.
	Niacin or fibrates can be used to lower non-HDL after LDL therapy is begun.	IIa (B)
	Omega-3 fish oil, 1 g/d is reasonable. Greater amounts (>2.5/d) are needed for elevated TG levels.	IIb (B)	1g fish oil means the sum of EPA + DHA, not total marine oil. Most people consume too little, even from supplements. More usually offers better protection against SCD. Omega-3 fats are pleiotropic.
	TG > 500 mg/dL should be addressed first to avoid pancreatitis with fibrates or niacin.	I (C)
Weight control	Keep BMI between 18.5–24.0 kg/m^2. Aim for a 10% reduction first. Be persistent and measure waist circumference. If it is ≥40″ (102 cm) in men or 35″ (89 cm) in women, consider MetS, especially in men with waists 37–40″ (94–102 cm) with genetic insulin resistance.	I (B)	Sustained weight control, since there is no truly effective pharmacologic therapy, is most difficult to achieve without surgery, but it is fundamental to risk reduction.
Physical activity	Recommend 30–60 min of moderate-intensity aerobic activity, 7 d/wk, a minimum of 5 d/wk, supplemented by an increase in daily activities. An activity history should be recorded, and an exercise test is performed to guide the exercise prescription. CR programs should be recommended for at-risk patients such as recent ACS or revascularization, or HF.	I (B)
	Resistance training 2 d/wk may be reasonable.	IIb (C)	3 days of strength training 45–60 min each session is usually the eventual goal if medically appropriate.
Diabetes	Keep HbA1c levels “near normal”	I (B)	ACCORD and other studies have recently modified views on the merits of very tight control.^Citation39,Citation207,Citation208 HbA1c guidelines from the ADA remain intact presently.
	Reduction of other risk factors (weight, physical activity, dyslipidemia, and BP should be vigorously pursued as recommended).
β blockers	Begin and continue indefinitely in all patients with prior AMI, ACS, or LV dysfunction with or without HF symptoms unless contraindicated.	I (A)	See discussion above concerning β blockers.
Antiplatelet agents	72–162 mg aspirin should be used in all patients and be continued indefinitely unless contraindicated.	I (A)	Use in primary prevention is controversial.
	Use with warfarin, and clopidogrel may increase bleeding and should be monitored.	I (B)	Genetic variation in responsiveness is now of clinical importance. Use of PPIs with clopidogrel is debated, and there is an FDA warning.
RAA system blockers	ACEI should be used in all patients with LVEF ≤ 40% in all patients and in those with HTN, DM, or CKD.	I (A)
	ARB should be used for those with HTN with indications but who cannot tolerate ACEI, have HF, or are post-MI with LVEF ≤ 40%.
	Aldosterone blockers should be used in post-MI patients without creatinine >2.5 mg/dL in men, >2 mg/dL in women, or K^+ > 5 mEq/L, who are receiving adequate doses of an ACEI and a β-blocker, have LVEF ≤ 40%, and have either DM or HF.
	ACEI for patients who are not low risk, ie, normal LVEF and in whom risk factors are controlled and revascularization has been performed.	I (B)	For patients who have not sustained an AMI, use of ACEI or ARB in angina patients is not established.
Vaccination	Influenza vaccination-recommended annually.	I (B)

Notes: There are 5 treatments that are considered class I (A), ie, should be done in all patients. There are no lifestyle recommendations that are I (A), and specific diet changes are not addressed. Currently available data concerning diet and lifestyle do not permit such classifications, but are potent therapies.

a COR, classifications of recommendations is as follows: class I, benefit ⋙ risk, and treatment should be done; class IIa, benefit ≫ risk, and it is reasonable; class IIb, benefit ≥ risk, and it may be considered; class II, risk ≥ benefit, and the treatment should not be done since it is not helpful and may harm. Class III items have been omitted. LOE, level of evidence, an estimate of certainty of treatment effect, is as follows: level A, useful in different subpopulations, with general consistency of direction and magnitude of effect; level B, only 2 to 3 subpopulations or risk strata have been evaluated; level C, limited, with 1 to 2 subpopulations evaluated. Classification as levels B or C does not imply ineffectiveness or weakness of the recommendation, simply that clinical trials have not been performed.

Abbreviations: ACC, American College of Cardiology; AHA, American Heart Association; COR, classifications of recommendations; LOE, level of evidence; BP, blood pressure; DM, diabetes mellitus; CKD, chronic renal disease; CHD, coronary heart disease; ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; LDL, low-density lipoprotein; TFA, trans fatty acids; TG, triglycerides; HDL, high-density lipoprotein; BMI, body mass index; SCD, sudden cardiac death; CR, supervised cardiac rehabilitation programs; ACS, acute coronary syndrome; HF, heart failure; ADA, American Diabetes Association; AMI, acute myocardial infarction; PPIs, proton pump inhibitors; FDA, Food and Drug Administration; RAA, renin-angiotensin-aldosterone; ACEI, angiotensin-converting enzyme inhibitor; LVEF, left ventricular ejection fraction; HTN, hypertension; MI, myocardial infarction; K⁺, serum potassium level.

Table 6 Relative contributions of risk factors to risk of AMI in the INTERHEART studya,¹⁶⁶

Risk factor	Odds ratio	Population attributable risk
Smoking	2.87 (for current vs never)	35.7% (for current and former vs never)
Raised ApoB/ApoA1 ratio	3.25 (for top vs lowest quintile)	49.2% (for top 4 quintiles vs lowest quintile)
History of hypertension	1.91	17.9%
Diabetes	2.37	9.9%
Abdominal obesity	1.12 (for top vs lowest tertile) 1.62 (for middle vs lowest tertile)	20.1% (for top 2 tertiles vs lowest tertile)
Psychosocial factors	2.67	32.5%
Daily consumption of fruits and vegetables	0.70	13.7% (for lack of daily consumption)
Regular alcohol consumption	0.91	6.7%
Regular physical activity	0.86	12.2%

a All risk factors were significantly related to AMI (P < 0.0001 for all risk factors and P = 0.03 for alcohol).

Abbreviation: AMI, acute myocardial infarction.

Table 8 ACC/AHA recommendations for PCI in patients with chronic stable angina⁴

Recommendations	Class I LOE
2-vessel or 3-vessel disease with significant proximal LAD lesions, with anatomy enabling catheter-based therapy and normal LVF; diabetics under treatment excluded.	I (B)
1-vessel or 2-vessel disease without significant proximal LAD lesions, with high risk on noninvasive testing and a large area of viable myocardium.	I (B)
Prior PCI with either recurrence of stenosis or high risk on noninvasive testing.	I (C)
Failure of optimum medical therapy and with acceptable risk for revascularization procedure.	I (B)

Abbreviations: ACC/AHA, American College of Cardiology/American Heart Association; PCI, percutaneous coronary intervention; LOE, level of evidence; LAD, left anterior descending coronary artery; LVF, left ventricular function.

Table 9 Extent of CAD in nonresistance vessels, 5-year survival rate (%), and prognostic weight (0–100), based upon medical therapy only²⁴²

Extent of CAD	5-year survival (%)	Prognostic weight (0–100)
1-vessel disease, 75%	93	23
>1-vessel disease, 50%–74%	93	23
1-vessel disease, ≥95%	91	32
2-vessel disease	88	37
2-vessel disease, both ≥95%	86	42
1-vessel disease, ≥95% proximal LAD	83	48
2-vessel disease, ≥95% LAD	83	48
2-vessel disease, ≥95% proximal LAD	79	56
3-vessel disease	79	56
3-vessel disease, ≥95% in at least 1	73	63
3-vessel disease, 75% proximal LAD	67	67
3-vessel disease, ≥95% proximal LAD	59	74

Abbreviations: CAD, coronary artery disease; LAD, Left anterior descending.

Table 10 Selected ACC/AHA guidelines for revascularization with CABG⁵

Recommendations for CABG	Class and level of evidence
Significant left main coronary disease.	I (A)
Triple-vessel disease; survival benefit is greater in patients with LVEF < 50%	I (A)
Double-vessel disease with significant proximal LAD disease and either LVEF < 50% or demonstrable ischemic on noninvasive testing.	I (A)
1- or 2-vessel disease without significant proximal LAD lesions, with high risk on noninvasive testing and a large area of viable myocardium.	I (B)
1- or 2-vessel disease without significant proximal LAD lesions who have survived SCD or sustained VT.	I (C)
Failure of optimum medical therapy and with acceptable risk for a revascularization procedure.	I (B)
1- or 2-vessel disease without significant proximal LAD Lesions, but with a moderate area of viable myocardium and demonstrable ischemia on noninvasive testing.	IIa (B)
Single vessel disease with significant proximal LAD disease.	IIa (B)

Abbreviations: ACC/AHA, American College of Cardiology/American Heart Association; CABG, coronary artery bypass surgery; LAD, Left anterior descending; LVEF, left ventricular ejection fraction; SCD, sudden cardiac death; VT, ventricular tachycardia.

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