Preventative Cardiology and Ischemic Heart Disease

GENERAL PRINCIPLES

Definition

Hypertension is defined as the presence of a blood pressure (BP) elevation to a level that places patients at increased risk for target organ damage in several vascular beds including the retina, brain, heart, kidneys, and large conduit arteries (Table 1).

Classification

Normal BP is defined as systolic blood pressure (SBP) < 120 mm Hg and diastolic blood pressure (DBP) < 80 mm Hg; pharmacologic intervention is not indicated.

Prehypertension is defined as SBP 120 to 139 mm Hg or DBP 80 to 89 mm Hg. These patients should engage in comprehensive lifestyle modifications to delay progression or prevent the development of hypertension. Pharmacologic therapy should be initiated in prehypertensive patients with evidence of target organ damage or diabetes.

In stage 1 (SBP 140 to 159 mm Hg or DBP 90 to 99 mm Hg) and stage 2 (SBP > 160 mm Hg or DBP > 100 mm Hg) hypertension, pharmacologic therapy should be initiated in addition to lifestyle modification to lower BP below 140/90 mm Hg in patients without diabetes or chronic kidney disease. In patients with diabetes or chronic kidney disease, BP should be lowered below 130/80 mm Hg. Patients with BP levels more than 20/10 mm Hg above their treatment target will often require more than one medication to achieve adequate control. Patients with an average BP of 200/120 mm Hg or greater require immediate therapy and, if symptomatic end-organ damage is present, hospitalization.

Hypertensive crisis includes hypertensive emergencies and urgencies. It usually develops in patients with a previous history of elevated BP but may arise in those who were previously normotensive. The severity of a hypertensive crisis correlates not only with the absolute level of BP elevation, but also with the rapidity of development, because autoregulatory mechanisms have not had sufficient time to adapt.

Hypertensive urgencies are defined as a substantial increase in BP, usually with a DBP >120 mm Hg, and occur in approximately 1% of hypertensive patients. Hypertensive urgencies (i.e., upper levels of stage 2 hypertension, hypertension with optic disk edema, progressive end-organ complications rather than damage, and severe perioperative hypertension) warrant BP reduction within several hours (JAMA 2003;289:2560-2572).

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Hypertensive emergencies include accelerated hypertension, typically defined as an SBP > 210 mm Hg and DBP > 130 mm Hg presenting with headaches, blurred vision, or focal neurologic symptoms, and malignant hypertension (which requires the presence of papilledema). Hypertensive emergencies require immediate BP reduction by 20% to 25% to prevent or minimize end-organ damage (i.e., hypertensive encephalopathy, intracranial hemorrhage, unstable angina [UA] pectoris, acute myocardial infarction [MI], acute left ventricular failure with pulmonary edema, dissecting aortic aneurysm, progressive renal failure, or eclampsia).

Isolated systolic hypertension, defined as an SBP > 140 mm Hg and normal DBP, occurs frequently in the elderly (beginning after the fifth decade and increasing with age). Nonpharmacologic therapy should be initiated with medications added as needed to lower SBP to <140 mm Hg. Patient tolerance of antihypertensive therapy should be assessed frequently.

Table 1 Manifestations of Target Organ Disease

Organ System

Manifestations

Large vessels

Aneurysmal dilation

Accelerated atherosclerosis

Aortic dissection

Cardiac

Acute

Pulmonary edema, myocardial infarction

Chronic

Clinical or ECG evidence of CAD; LVH by ECG or echocardiogram

Cerebrovascular

Acute

Intracerebral bleeding, coma, seizures, mental status changes, TIA, stroke

Chronic

TIA, stroke

Renal

Acute

Hematuria, azotemia

Chronic

Serum creatinine > 1.5 mg/dL, proteinuria > 1+ on dipstick

Retinopathy

Acute

Papilledema, hemorrhages

Chronic

Hemorrhages, exudates, arterial nicking

CAD, coronary artery disease; ECG, electrocardiogram; LVH, left ventricular hypertrophy; TIA, transient ischemic attack.

Epidemiology

The public health burden of hypertension is enormous, affecting an estimated 60.5 million Americans adults (Wong ND. Arch Intern Med 2007;167:2431-2436). Indeed, for nonhypertensive individuals aged 55 to 65 years of age, the lifetime risk of developing hypertension is 90% (Vasan RS, et al. JAMA 2002;287:1003-1010).

Data derived from the Framingham study have shown that hypertensive patients have a fourfold increase in cerebrovascular accidents, as well as a sixfold increase in congestive heart failure (CHF) when compared to normotensive control subjects.

Disease-associated morbidity and mortality, including atherosclerotic cardiovascular disease, stroke, heart failure (HF), and renal insufficiency, increase with higher levels of SBP and DBP.

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Over the past three decades, aggressive treatment of hypertension has resulted in a substantial decrease in death rates from stroke and coronary heart disease. Unfortunately, rates of end-stage renal disease and hospitalization for CHF have continued to increase. BP control rates remain poor with only 34% of treated hypertensive patients below their goal BP level (Ong KL, et al. HTN 2007;49:69-75).

Etiology

Of all hypertensive patients, more than 90% have primary or essential hypertension; the remainder have secondary hypertension due to causes such as renal parenchymal disease, renovascular disease, pheochromocytoma, Cushing's syndrome, primary hyperaldosteronism, coarctation of the aorta, obstructive sleep apnea, and uncommon autosomal dominant or autosomal recessive diseases of the adrenal-renal axis that result in salt retention.

Risk Factors

BP rises with age. Other contributing factors include overweight/obesity, increased dietary sodium intake, decreased physical activity, increased alcohol consumption, and lower dietary intake of fruits, vegetables, and potassium.

Prevention

Prevention should be focused on risk factor modification. Strategies must address cultural and social barriers related to health care delivery and behavioral modification.

DIAGNOSIS

Clinical Presentation

BP elevation is usually discovered in asymptomatic individuals during routine health visits.

Optimal detection and evaluation of hypertension requires accurate noninvasive BP measurement, which should be obtained in a seated patient with the arm resting level with the heart. A calibrated, appropriately fitting BP cuff (inflatable bladder encircling at least 80% of the arm) should be used because falsely high readings can be obtained if the cuff is too small.

Two readings should be taken, separated by 2 minutes. SBP should be noted with the appearance of Korotkoff sounds (phase I) and DBP with the disappearance of sounds (phase V).

In certain patients, the Korotkoff sounds do not disappear but are present to 0 mm Hg. In this case, the initial muffling of Korotkoff sounds (phase IV) should be taken as the DBP. One should be careful to avoid reporting spuriously low BP readings due to an auscultatory gap, which is caused by the disappearance and reappearance of Korotkoff sounds in hypertensive patients and may account for up to a 25-mm Hg gap between true and measured SBP. Hypertension should be confirmed in both arms, and the higher reading should be used.

History

The history should seek to discover secondary causes of hypertension and note the presence of medications that can affect BP (e.g., decongestants, oral contraceptives, appetite suppressants, nonsteroidal anti-inflammatory agents, exogenous

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thyroid hormone, recent alcohol consumption, caffeine anabolic steroids, and illicit stimulants such as cocaine).

A diagnosis of secondary hypertension should be considered in the following situations:

Age at onset younger than 30 or older than 60 years

Hypertension that is difficult to control after therapy has been initiated

Stable hypertension that becomes difficult to control

Clinical occurrence of a hypertensive crisis

The presence of signs or symptoms of a secondary cause such as hypokalemia or metabolic alkalosis that is not explained by diuretic therapy

In patients who present with significant hypertension at a young age, a careful family history may give clues to forms of hypertension that follow simple Mendelian inheritance.

Physical Examination

The physical examination should include investigation for target organ damage or a secondary cause of hypertension by noting the presence of carotid bruits, an S3 or S4, cardiac murmurs, neurologic deficits, elevated jugular venous pressure, rales, retinopathy, unequal pulses, enlarged or small kidneys, cushingoid features, and abdominal bruits. Overweight/obesity should be assessed by measurement of height and weight, and/or abdominal waist circumference.

Differential Diagnosis

Hypertension may be part of several important syndromes of withdrawal from drugs, including alcohol, cocaine, and opioid analgesics. Rebound increases in BP also may be seen in patients who abruptly discontinue antihypertensive therapy, particularly β-adrenergic antagonists and central α2-agonists (see Complications).

Cocaine and other sympathomimetic drugs (e.g., amphetamines, phencyclidine hydrochloride) can produce hypertension in the setting of acute intoxication and when the agents are discontinued abruptly after chronic use. Hypertension is often complicated by other end-organ insults, such as ischemic heart disease, stroke, and seizures. Phentolamine is effective in acute management, and sodium nitroprusside or nitroglycerin can be used as an alternative (Table 2). β-Adrenergic antagonists should be avoided due to the risk of unopposed α-adrenergic activity, which can exacerbate hypertension.

Diagnostic Testing

Laboratories

Tests are needed to help identify patients with possible target organ damage, to help assess cardiovascular risk, and to provide a baseline for monitoring the adverse effects of therapy:

Urinalysis

Hematocrit

Plasma glucose

Serum potassium

Serum creatinine

Calcium

Uric acid

Fasting lipid levels

Electrocardiogram (ECG)

Chest radiography

Echocardiography may be of value for certain patients to assess cardiac function or detection of left ventricular hypertrophy (LVH)

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Table 2 Commonly Used Antihypertensive Agents by Functional Class

Drugs by Class

Properties

Initial Dose

Usual Dosage Range (mg)

β-Adrenergic antagonists

Atenolola,b

Selective

50 mg PO daily

25-100

Betaxolol

Selective

10 mg PO daily

5-40

Bisoprolola

Selective

5 mg PO daily

2.5-20

Metoprolol

Selective

50 mg PO bid

50-450

Metoprolol XL

Selective

50-100 mg PO daily

50-400

Nebivolol

Selective with vasodilatory properties

5 mg PO daily

5-40

Nadolola

Nonselective

40 mg PO daily

20-240

Propranololb

Nonselective

40 mg PO bid

40-240

Propranolol LA

Nonselective

80 mg PO daily

60-240

Timololb

Nonselective

10 mg PO bid

20-40

Carteolola

ISA

2.5 mg PO daily

2.5-10

Penbutolol

ISA

20 mg PO daily

20-80

Pindolol

ISA

5 mg PO daily

10-60

Labetalol

α- and β-antagonist properties

100 mg PO bid

200-1,200

Carvedilol

α- and β-antagonist properties

6.25 mg PO bid

12.5-50

Acebutolola

ISA, selective

200 mg PO bid, 400 mg PO daily

200-1,200

Calcium channel antagonists

Amlodipine

DHP

5 mg PO daily

2.5-10

Diltiazem

30 mg PO qid

90-360

Diltiazem

SR 60-120 mg PO bid

120-360

Diltiazem

CD 180 mg PO bid

180-360

Diltiazem

XR 80 mg daily

180-480

Isradipine

DHP

2.5 mg PO bid

2.5-10

Nicardipineb

DHP

20 mg PO tid

60-120

Nicardipine SR

DHP

30 mg PO bid

60-120

Nifedipine

DHP

10 mg PO tid

30-120

Nifedipine XL (or CC)

DHP

30 mg PO daily

30-90

Nisoldipine

DHP

20 mg PO daily

20-40

Verapamilb

80 mg PO tid

80-480

Verapamil COER

80 mg PO daily

180-480

Verapamil SR

120-140 mg PO daily

120-480

Angiotensin-converting enzyme inhibitors

Benazeprila

10 mg PO bid

10-40

Captoprila

25 mg PO bid-tid

50-450

Enalaprila

5 mg PO daily

2.5-40

Fosinopril

10 mg PO daily

10-40

Lisinoprila

10 mg PO daily

5-40

Moexipril

7.5 mg PO daily

7.5-30

Quinaprila

10 mg PO daily

5-80

Ramiprila

2.5 mg PO daily

1.25-20

Trandolapril

1-2 mg PO daily

1-4

Angiotensin II receptor blocker

Candesartan

8 mg PO daily

8-32

Eprosartan

600 mg PO daily

600-800

Irbesartan

150 mg PO daily

150-300

Olmesartan

20 mg PO daily

20-40

Losartan

50 mg PO daily

25-100

Telmisartan

40 mg PO daily

20-80

Valsartan

80 mg PO daily

80-320

Diuretics

Bendroflumethiazide

Thiazide diuretic

5 mg PO daily

2.5-15

Benzthiazide

Thiazide diuretic

25 mg PO bid

50-100

Chlorothiazide

Thiazide diuretic

500 mg PO daily (or IV)

125-1,000

Chlorthalidone

Thiazide diuretic

25 mg PO daily

12.5-50

Hydrochlorothiazide

Thiazide diuretic

12.5 mg PO daily

12.5-50

Hydroflumethiazide

Thiazide diuretic

50 mg PO daily

50-100

Indapamide

Thiazide diuretic

1.25 mg PO daily

2.5-5.0

Methyclothiazide

Thiazide diuretic

2.5 mg PO daily

2.5-5.0

Metolazone

Thiazide diuretic

2.5 mg PO daily

1.25-5

Polythiazide

Thiazide diuretic

2.0 mg PO daily

1-4

Quinethazone

Thiazide diuretic

50 mg PO daily

25-100

Trichlormethiazide

Thiazide diuretic

2.0 mg PO daily

1-4

Bumetanide

Loop diuretic

0.5 mg PO daily (or IV)

0.5-5

Ethacrynic acid

Loop diuretic

50 mg PO daily (or IV)

25-100

Furosemide

Loop diuretic

20 mg PO daily (or IV)

20-320

Torsemide

Loop diuretic

5 mg PO daily (or IV)

5-10

Amiloride

Potassium-sparing diuretic

5 mg PO daily

5-10

Triamterene

Potassium-sparing diuretic

50 mg PO bid

50-200

Eplerenone

Aldosterone antagonist

25 mg PO daily

25-100

Spironolactone

Aldosterone antagonist

25 mg PO daily

25-100

α-Adrenergic antagonists

Doxazosin

1 mg PO daily

1-16

Prazosin

1 mg PO bid-tid

1-20

Terazosin

1 mg PO at bedtime

1-20

Centrally acting adrenergic agents

Clonidineb

0.1 mg PO bid

0.1-1.2

Clonidine patch

TTS 1/wk (equivalent to 0.1 mg/d release)

0.1-0.3

Guanfacine

1 mg PO daily

1-3

Guanabenz

4 mg PO bid

4-64

Methyldopab

250 mg PO bid-tid

250-2,000

Direct-acting vasodilators

Hydralazine

10 mg PO qid

50-300

Minoxidil

5 mg PO daily

2.5-100

Miscellaneous

Reserpineb

0.5 mg PO daily

0.01-0.25

DHP, dihydropyridine; ISA, intrinsic sympathomimetic activity; TTS, transdermal therapeutic system.

a Adjusted in renal failure.

b Available in generic form.

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TREATMENT

Behavioral

Nonpharmacologic therapy. Lifestyle modifications should be encouraged in all hypertensive patients regardless of whether they require medication. These changes may have beneficial effects on other cardiovascular risk factors. Some of these lifestyle modifications include cessation of smoking, reduction in body weight if the patient is overweight, judicious consumption of alcohol, adequate nutritional intake of minerals and vitamins, reduction in sodium intake, and increased physical activity.

Medications

Initial drug therapy. Data from the ALLHAT trial have shown decreased cardiovascular and cerebrovascular morbidity and mortality with the use of thiazide diuretics (JAMA 2002;288:2981-2997); thus, this class of drug is favored as first-line therapy unless there is a contraindication to their use or the characteristics of a patient's profile (concomitant disease, age, race) mandate the institution of a different agent.

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Calcium channel antagonists and angiotensin-converting enzyme (ACE) inhibitors have a low side-effect profile and have been shown to decrease BP to degrees similar to those observed with diuretics and β-adrenergic antagonists. In ALLHAT, reductions in morbidity and mortality were similar to diuretics making them reasonable initial agents. In patients with stage 2 hypertension, therapy may be initiated with a two-drug combination, typically a thiazide diuretic plus a calcium antagonist, ACE inhibitor, or β-adrenergic antagonists. Initial drug choice may be affected by coexistent factors, such as age, race, angina, HF, renal insufficiency, LVH, obesity, hyperlipidemia, gout, and bronchospasm. Cost and drug interactions should also be considered. The BP response is usually consistent within a given class of agents; therefore, if a drug fails to control BP, another agent from the same class is unlikely to be effective. At times, however, a change within drug class may be useful in reducing adverse effects. The lowest possible effective dosage should be used to control BP, adjusted every 1 to 3 months as needed.

Additional therapy. When a second drug is needed, it should generally be chosen from among the other first-line agents. A diuretic should be added first, as doing so may enhance effectiveness of the first drug, yielding more than a simple additive effect.

Adjustments of a therapeutic regimen. In considering a modification of therapy because of inadequate response to the current regimen, the physician should investigate other possible contributing factors. Poor patient compliance, use of antagonistic drugs (i.e., sympathomimetics, antidepressants, steroids, nonsteroidal anti-inflammatory drugs [NSAIDs], cyclosporine, caffeine, thyroid hormones, cocaine, erythropoietin), inappropriately high sodium intake, or increased alcohol consumption should be considered before antihypertensive drug therapy is modified. Secondary causes of hypertension must be considered when a previously effective regimen becomes inadequate and other confounding factors are absent.

Diuretics (Table 2) are effective agents in the therapy of hypertension, and data have accumulated to demonstrate their safety and benefit in reducing the incidence of stroke and cardiovascular events.

Several classes of diuretics are available, generally categorized by their site of action in the kidney. Thiazide and thiazide-like diuretics (e.g., hydrochlorothiazide, chlorthalidone) block sodium reabsorption predominantly in the distal convoluted tubule by inhibition of the thiazide-sensitive Na/Cl cotransporter. Loop diuretics (e.g., furosemide, bumetanide, ethacrynic acid, and torsemide) block sodium reabsorption in the thick ascending loop of Henle through inhibition of the Na/K/2Cl cotransporter and are the most effective agents in patients with renal insufficiency (estimated glomerular filtration rate [eGFR] < 35 mL/min/1.73 m2). Spironolactone and eplerenone, potassium-sparing agents, act by competitively inhibiting the actions of aldosterone on the kidney. Triamterene and amiloride are potassium-sparing drugs that inhibit the epithelial Na+ channel in the distal nephron to inhibit reabsorption of Na+ and secretion of potassium ions. Potassium-sparing diuretics are weak agents when used alone; thus, they are often combined with a thiazide for added potency. Aldosterone antagonists may have an additional benefit in improving myocardial function in HF; this effect may be independent of its effect on renal transport mechanisms.

Side effects of diuretics vary by class. Thiazide diuretics can produce weakness, muscle cramps, and impotence. Metabolic side effects include hypokalemia, hypomagnesemia, hyperlipidemia (with increases in low-density lipoproteins [LDLs] and triglyceride levels), hypercalcemia, hyperglycemia, hyperuricemia,

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hyponatremia, and, rarely, azotemia. Thiazide-induced pancreatitis has also been reported. Metabolic side effects may be limited when thiazides are used in low doses (e.g., hydrochlorothiazide, 12.5 to 25.0 mg/d). Loop diuretics can cause electrolyte abnormalities such as hypomagnesemia, hypocalcemia, and hypokalemia, and can also produce irreversible ototoxicity (usually dose related and more common with parenteral therapy). Spironolactone and eplerenone can produce hyperkalemia; however, the gynecomastia that may occur in men and breast tenderness in women are not seen with eplerenone. Triamterene (usually in combination with hydrochlorothiazide) can cause renal tubular damage and renal calculi. Unlike thiazides, potassium-sparing and loop diuretics do not cause adverse lipid effects.

β-Adrenergic antagonists (Table 2) are effective antihypertensive agents and are part of medical regimens that have been proven to decrease the incidence of stroke, MI, and HF.

The mechanism of action of β-adrenergic antagonists is competitive inhibition of the effects of catecholamines at β-adrenergic receptors, which decreases heart rate and cardiac output. These agents also decrease plasma renin and cause a resetting of baroreceptors to accept a lower level of BP. β-Adrenergic antagonists cause release of vasodilatory prostaglandins, decrease plasma volume, and may also have a central nervous system (CNS)-mediated antihypertensive effect.

Classes of β-adrenergic antagonists can be subdivided into those that are cardioselective, with primarily β1-blocking effects, and those that are nonselective, with β1- and β2-blocking effects. At low doses, the cardioselective agents can be given with caution to patients with mild chronic obstructive pulmonary disease, diabetes mellitus (DM), or peripheral vascular disease. At higher doses, these agents lose their β1 selectivity and may cause unwanted effects in these patients. β-Adrenergic antagonists can also be categorized according to the presence or absence of partial agonist or intrinsic sympathomimetic activity (ISA). β-Adrenergic antagonists with ISA cause less bradycardia than do those without it. In addition, there are agents with mixed properties having both α- and β-adrenergic antagonist actions (labetalol and carvedilol). Nebivolol is a highly selective β-adrenergic antagonist that is vasodilatory through an unclear mechanism.

Side effects include high-degree atrioventricular (AV) block, HF, Raynaud's phenomenon, and impotence. Lipophilic β-adrenergic antagonists, such as propranolol, have a higher incidence of CNS side effects including insomnia and depression. Propranolol can also cause nasal congestion. β-Adrenergic antagonists can cause adverse effects on the lipid profile; increased triglyceride and decreased high-density lipoprotein (HDL) levels occur mainly with nonselective β-adrenergic antagonists but generally do not occur when β-adrenergic antagonists with ISA are used. Pindolol, a selective β-adrenergic antagonist with ISA, may actually increase HDL and nominally increase triglycerides. Side effects of labetalol include hepatocellular damage, postural hypotension, a positive antinuclear antibody (ANA) test, a lupus-like syndrome, tremors, and potential hypotension in the setting of halothane anesthesia. Carvedilol appears to have a similar side-effect profile to other β-adrenergic antagonists. Both labetalol and carvedilol have negligible effects on lipids. Rarely, reflex tachycardia may occur because of the initial vasodilatory effect of labetalol and carvedilol. Because β-receptor density is increased with chronic antagonism, abrupt withdrawal of these agents can precipitate angina pectoris, increases in BP, and other effects attributable to an increase in adrenergic tone.

Selective α-adrenergic antagonists such as prazosin, terazosin, and doxazosin have replaced nonselective α-adrenergic antagonists such as phenoxybenzamine

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(Table 2) in the treatment of essential hypertension. Based on the ALLHAT trial, these drugs appear to be less efficacious than diuretics, calcium channel blockers, and ACE inhibitors in reducing primary end points of cardiovascular disease when used as monotherapy (JAMA 2002;283:1967-1975; JAMA 2002;288:2981-2997).

Side effects of these agents include a “first-dose effect,” which results from a greater decrease in BP with the first dose than with subsequent doses. Selective α1-adrenergic antagonists can cause syncope, orthostatic hypotension, dizziness, headache, and drowsiness. In most cases, side effects are self-limited and do not recur with continued therapy. Selective α1-adrenergic antagonists may improve lipid profiles by decreasing total cholesterol and triglyceride levels and increasing HDL levels. Additionally, these agents can improve the negative effects on lipids induced by thiazide diuretics and β-adrenergic antagonists. Doxazosin specifically may be less effective in lowering SBP than thiazide diuretics and may additionally be associated with a higher risk of cardiovascular disease, particularly HF and stroke in patients with hypertension and at least one additional risk factor for coronary artery disease (CAD) (JAMA 2002;283:1967-1975).

Centrally acting adrenergic agents (Table 2) are potent antihypertensive agents. In addition to its oral dosage forms, clonidine is available as a transdermal patch that is applied weekly.

Side effects may include bradycardia, drowsiness, dry mouth, orthostatic hypotension, galactorrhea, and sexual dysfunction. Transdermal clonidine causes a rash in up to 20% of patients. These agents can precipitate HF in patients with decreased left ventricular function, and abrupt cessation can precipitate an acute withdrawal syndrome (AWS) of elevated BP, tachycardia, and diaphoresis (see Complications). Methyldopa produces a positive direct antibody (Coombs) test in up to 25% of patients, but significant hemolytic anemia is much less common. If hemolytic anemia develops secondary to methyldopa, the drug should be withdrawn. Severe cases of hemolytic anemia may require treatment with glucocorticoids. Methyldopa also causes positive ANA test results in approximately 10% of patients and can cause an inflammatory reaction in the liver that is indistinguishable from viral hepatitis; fatal hepatitis has been reported. Guanabenz and guanfacine decrease total cholesterol levels, and guanfacine can also decrease serum triglyceride levels.

Reserpine, guanethidine, and guanadrel (Table 2) were among the first effective antihypertensive agents available. Currently, these drugs are not regarded as first- or second-line therapy because of their significant side effects.

Side effects of reserpine include severe depression in approximately 2% of patients. Sedation and nasal stuffiness also are potential side effects. Guanethidine can cause severe postural hypotension through a decrease in cardiac output, a decrease in peripheral resistance, and venous pooling in the extremities. Patients who are receiving guanethidine with orthostatic hypotension should be cautioned to arise slowly and to wear support hose. Guanethidine can also cause ejaculatory failure and diarrhea.

Calcium channel antagonists (Table 2) are effective agents in the treatment of hypertension. Generally, they have no significant CNS side effects and can be used to treat diseases, such as angina pectoris, that can coexist with hypertension. Due to the concern that the use of short-acting dihydropyridine calcium channel antagonists may increase the number of ischemic cardiac events, they are not indicated for hypertension management (JAMA 1995;274:620-625); long-acting agents are considered safe in the management of hypertension (Am J Cardiol 1996;77:81-82).

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Classes of calcium channel antagonists include diphenylalkylamines (e.g., verapamil), benzothiazepines (e.g., diltiazem), and dihydropyridines (e.g., nifedipine). The dihydropyridines include many newer second-generation drugs (e.g., amlodipine, felodipine, isradipine, and nicardipine), which are more vasoselective and have longer plasma half-lives than nifedipine. Verapamil and diltiazem have negative cardiac inotropic and chronotropic effects. Nifedipine also has a negative inotropic effect but in clinical use this effect is much less pronounced than that of verapamil or diltiazem because of peripheral vasodilation and reflex tachycardia. Less negative inotropic effects have been observed with the second-generation dihydropyridines. All calcium channel antagonists are metabolized in the liver; thus in patients with cirrhosis, the dosing interval should be adjusted accordingly. Some of these drugs also inhibit the metabolism of other hepatically cleared medications (e.g., cyclosporine). Verapamil and diltiazem should be used with caution in patients with cardiac conduction abnormalities as they can worsen HF in patients with decreased left ventricular function.

Side effects of verapamil include constipation, nausea, headache, and orthostatic hypotension. Diltiazem can cause nausea, headache, and rash. Dihydropyridines can cause lower extremity edema, flushing, headache, and rash. Calcium channel antagonists have no significant effects on glucose tolerance, electrolytes, or lipid profiles. In general, calcium channel antagonists should not be initiated in patients immediately after MI because of increased mortality in all but the most stable patients without evidence of HF.

Inhibitors of the renin-angiotensin system (Table 2) are effective antihypertensive agents in a broad array of patients.

ACE inhibitors may have beneficial effects in patients with concomitant HF or kidney disease. One study has also suggested that ACE inhibitors (ramipril) may significantly reduce the rate of death, MI, and stroke in patients without HF or low ejection fraction (N Engl J Med 2000;342:145-153). Additionally, they can reduce hypokalemia, hypercholesterolemia, hyperglycemia, and hyperuricemia caused by diuretic therapy and are particularly effective in states of hypertension associated with a high renin state (e.g., scleroderma renal crisis).

Side effects associated with the use of ACE inhibitors are infrequent. They can cause a dry cough (up to 20% of patients), angioneurotic edema, and hypotension, but they do not cause levels of lipids, glucose, or uric acid to increase. ACE inhibitors that contain a sulfhydryl group (e.g., captopril) may cause taste disturbance, leukopenia, and a glomerulopathy with proteinuria. Because ACE inhibitors cause preferential vasodilation of the efferent arteriole in the kidney, worsening of renal function may occur in patients who have decreased renal perfusion or who have preexisting severe renal insufficiency. ACE inhibitors can cause hyperkalemia and should be used with caution in patients with a decreased GFR who are taking potassium supplements or who are receiving potassium-sparing diuretics.

Angiotensin receptor blockers (ARBs) are a class of antihypertensive drugs that are effective in diverse patient populations (N Engl J Med 1996;334:1649-1654). Several of these agents are now approved for the management of mild to moderate hypertension (Table 2). Additionally, ARBs may be useful alternatives in patients with HF who are unable to tolerate ACE inhibitors (N Engl J Med 2001;345:1667-1675).

Side effects of ARBs occur rarely but include angioedema, allergic reaction, and rash.

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Direct-acting vasodilators are potent antihypertensive agents (Table 2) now reserved for refractory hypertension or specific circumstances, such as the use of hydralazine in pregnancy. Hydralazine in combination with nitrates is useful in treating patients with hypertension and HF (see Chapter 4, Heart Failure, Cardiomyopathy, and Valvular Heart Disease).

Side effects of hydralazine therapy may include headache, nausea, emesis, tachycardia, and postural hypotension. Asymptomatic patients may have a positive ANA test result and a hydralazine-induced systemic lupus-like syndrome may develop in approximately 10% of patients. Patients who may be at increased risk for this latter complication include (i) those treated with excessive doses (e.g., >400 mg/d), (ii) those with impaired renal or cardiac function, and (iii) those with the slow acetylation phenotype. Hydralazine should be discontinued if clinical evidence of a lupus-like syndrome develops and a positive ANA test result is present. The syndrome usually resolves with discontinuation of the drug, leaving no adverse long-term effects. Side effects of minoxidil include weight gain, hypertrichosis, hirsutism, ECG abnormalities, and pericardial effusions.

Parenteral antihypertensive agents are indicated for the immediate reduction of BP in patients with hypertensive emergencies. Judicious administration of these agents (Table 3) may also be appropriate in patients with hypertension complicated by HF or MI. These drugs are also indicated for individuals who have perioperative hypertensive urgency or are in need of emergency surgery. If possible, an accurate baseline BP should be determined before the initiation of therapy. In the setting of hypertensive emergency, the patient should be admitted to an intensive care unit (ICU) for close monitoring, and an intra-arterial monitor should be used when available. Although parenteral agents are indicated as a first line in hypertensive emergencies, oral agents may also be effective in this group; the choice of drug and route of administration must be individualized. If parenteral agents are used initially, oral medications should be administered shortly thereafter to facilitate rapid weaning from parenteral therapy.

Sodium nitroprusside, a direct-acting arterial and venous vasodilator, is the drug of choice for most hypertensive emergencies (Table 3). It reduces BP rapidly and is easily titratable, and its action is short lived when discontinued. Patients should be monitored very closely to avoid an exaggerated hypotensive response. Therapy for more than 48 to 72 hours with a high cumulative dose or renal insufficiency may cause accumulation of thiocyanate, a toxic metabolite. Thiocyanate toxicity may cause paresthesias, tinnitus, blurred vision, delirium, or seizures. Serum thiocyanate levels should be kept at >10 mg/dL. Patients on high doses (>2 to 3 mg/kg/min) or those with renal dysfunction should have serum levels of thiocyanate drawn after 48 to 72 hours of therapy. In patients with normal renal function or those receiving lower doses, levels can be drawn after 5 to 7 days. Hepatic dysfunction may result in accumulation of cyanide, which can cause metabolic acidosis, dyspnea, vomiting, dizziness, ataxia, and syncope. Hemodialysis should be considered for thiocyanate poisoning. Nitrites and thiosulfate can be administered intravenously for cyanide poisoning.

Nitroglycerin given as a continuous IV infusion (Table 3) may be appropriate in situations in which sodium nitroprusside is relatively contraindicated, such as in patients with severe coronary insufficiency or advanced renal or hepatic disease. It is the preferred agent for patients with moderate hypertension in the setting of acute coronary ischemia or after coronary artery bypass surgery because of its more favorable effects on pulmonary gas exchange and collateral coronary blood

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flow. In patients with severely elevated BP, sodium nitroprusside remains the agent of choice. Nitroglycerin reduces preload more than afterload and should be used with caution or avoided in patients who have inferior MI with right ventricular infarction and are dependent on preload to maintain cardiac output.

Labetalol can be administered parenterally (Table 3) in hypertensive crisis, even in patients in the early phase of an acute MI, and is the drug of choice in hypertensive emergencies that occur during pregnancy. When given intravenously, the β-adrenergic antagonist effect is greater than the α-adrenergic antagonist effect. Nevertheless, symptomatic postural hypotension may occur with IV use, thus patients should be treated in a supine position. Labetalol may be particularly beneficial during adrenergic excess (e.g., clonidine withdrawal, pheochromocytoma, postcoronary bypass grafting). As the half-life of labetalol is 5 to 8 hours, intermittent IV bolus dosing may be preferable to IV infusion. IV infusion can be discontinued before oral labetalol is begun. When the supine DBP begins to rise, oral dosing can be initiated at 200 mg PO, followed in 6 to 12 hours by 200 to 400 mg PO, depending on the BP response.

Esmolol is a parenteral, short-acting, cardioselective β-adrenergic antagonist (Table 3) that can be used in the treatment of hypertensive emergencies in patients in whom β-blocker intolerance is a concern. Esmolol is also useful for the treatment of aortic dissection. β-Adrenergic antagonists may be ineffective when used as monotherapy in the treatment of severe hypertension and are frequently combined with other agents (e.g., with sodium nitroprusside in the treatment of aortic dissection).

Nicardipine is an effective IV calcium antagonist preparation (Table 3) approved for use in postoperative hypertension. Side effects include headache, flushing, reflex tachycardia, and venous irritation. Nicardipine should be administered via a central venous line. If it is given peripherally, the IV site should be changed q12h. Fifty percent of the peak effect is seen within the first 30 minutes, but the full peak effect is not achieved until after 48 hours of administration.

Enalaprilat is the active deesterified form of enalapril (Table 3) that results from hepatic conversion after an oral dose. Enalaprilat (as well as other ACE inhibitors) has been used effectively in cases of severe and malignant hypertension. However, variable and unpredictable results have also been reported. ACE inhibition can cause rapid BP reduction in hypertensive patients with high renin states such as renovascular hypertension, concomitant use of vasodilators, and scleroderma renal crisis; thus, Enalaprilat should be used cautiously to avoid precipitating hypotension. Therapy can be changed to an oral preparation when IV therapy is no longer necessary.

Diazoxide and hydralazine are only rarely used in hypertensive crises and offer little or no advantage to the agents discussed previously. It should be noted, however, that hydralazine is a useful agent in pregnancy-related hypertensive emergencies because of its established safety profile.

Fenoldopam is a selective agonist to peripheral dopamine-1 receptors, and it produces vasodilation, increases renal perfusion, and enhances natriuresis. Fenoldopam has a short duration of action; the elimination half-life is <10 minutes. The drug has important application as parental therapy for high-risk hypertensive surgical patients and the perioperative management of patients undergoing organ transplantation.

Oral loading of antihypertensive agents has been used successfully in patients with hypertensive crisis when urgent but not immediate reduction of BP is indicated.

Oral clonidine loading is achieved by using an initial dose of 0.2 mg PO followed by 0.1 mg PO q1h to a total dose of 0.7 mg or a reduction in diastolic pressure of 20 mm Hg or more. BP should be checked at 15-minute intervals over the first hour, 30-minute intervals over the second hour, and then hourly. After 6 hours, a diuretic can be added, and an 8-hour clonidine dosing interval can be begun. Sedative side effects are significant.

Sublingual nifedipine has an onset of action within 30 minutes but can produce wide fluctuations and excessive reductions in BP. Because of the potential for adverse cardiovascular events (stroke/MI), sublingual nifedipine should be avoided in the acute management of elevated BP. Side effects include facial flushing and postural hypotension.

Table 3 Parental Antihypertensive Drug Preparations

Drug

Administration

Onset

Duration of Action

Dosage

Adverse Effects and Comments

Fenoldopam

IV infusion

<5

min 30 min

0.1-0.3 mcg/kg/min

Tachycardia, nausea, vomiting

Sodium nitroprusside

IV infusion

Immediate

2-3 min

0.5-10 mcg/kg/min (initial dose, 0.25 mcg/kg/min for eclampsia and renal insufficiency)

Hypotension, nausea, vomiting, apprehension. Risk of thiocyanate and cyanide toxicity increased in renal and hepatic insufficiency, respectively; levels should be monitored. Must shield from light.

Diazoxide

IV bolus

15 min

6-12 hr

50-100 mg q5-10 min, up to 600 mg

Hypotension, tachycardia, nausea, vomiting, fluid retention, hyperglycemia. May exacerbate myocardial ischemia, heart failure, or aortic dissection.

Labetalol

IV bolus

5-10 min

3-6 hr

20-80 mg q5-10 min, up to 300 mg

Hypotension, heart block, heart failure, bronchospasm, nausea, vomiting, scalp tingling, paradoxical pressor response. May not be effective in patients receiving α- or β-antagonists.

IV infusion

0.5-2 mg/min

Nitroglycerin

IV infusion

1-2 min

3-5 min

5-250 mcg/min

Headache, nausea, vomiting. Tolerance may develop with prolonged use.

Esmolol

IV bolus

1-5 min

10 min

500 mcg/kg/min for first 1 min

Hypotension, heart block, heart failure, bronchospasm.

IV infusion

50-300 mcg/kg/min

Phentolamine

IV bolus

1-2 min

3-10 min

5-10 mg q5-15 min

Hypotension, tachycardia, headache, angina, paradoxical pressor response.

Hydralazine (for treatment of eclampsia)

IV bolus

10-20 min

3-6 hr

10-20 mg q20 min (if no effect after 20 mg, try another agent)

Hypotension, fetal distress, tachycardia, headache, nausea, vomiting, local thrombophlebitis. Infusion site should be changed after 12 hr.

Methyldopate (for treatment of eclampsia)

IV bolus

30-60 min

10-16 hr

250-500 mg

Hypotension

Nicardipine

IV infusion

1-5 min

3-6 hr

5 mg/hr, increased by 1.0-2.5 mg/hr q15 min, up to 15 mg/hr

Hypotension, headache, tachycardia, nausea, vomiting.

Enalaprilat

IV bolus

5-15 min

1-6 hr

0.6255 mg q6h

Hypotension

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Lifestyle/Risk Modification

General considerations and goals. The goal of treatment for hypertension is to prevent long-term sequelae (i.e., target organ damage). Barring an overt need for immediate pharmacologic therapy, most patients should be given the opportunity to achieve a reduction in BP over an interval of 3 to 6 months by applying nonpharmacologic modifications and pharmacologic therapies if needed. The primary goal is to reduce BP to <140/90 mm Hg while concurrently controlling other modifiable cardiovascular risk factors. As isolated systolic hypertension is also associated with increased cerebrovascular and cardiac events, the therapeutic goal in this subset of patients should be to lower BP to <140 mm Hg systolic. Treatment should be more aggressive in patients with chronic kidney disease or diabetes, with a goal BP of <130/80. Discretion is warranted in prescribing medication to lower BP that may affect cardiovascular risk adversely in other ways (e.g., glucose control, lipid metabolism, uric acid levels). In the absence of hypertensive crisis, BP should be reduced gradually to avoid end-organ (e.g., cerebral) ischemia.

SPECIAL CONSIDERATIONS

Protocol

Hypertensive crisis. In hypertensive emergency, control of acute or ongoing end-organ damage is more important than the absolute level of BP. BP control with a rapidly acting parenteral agent should be accomplished as soon as possible (within 1 hour) to reduce the chance of permanent organ dysfunction and death. A reasonable goal is a 20% to 25% reduction of mean arterial pressure or a reduction of the diastolic pressure to 100 to 110 mm Hg over a period of minutes to hours. A precipitous fall in BP may occur in patients who are elderly, volume depleted, or receiving other antihypertensive agents, and caution should be used to avoid cerebral hypoperfusion. BP control in hypertensive urgencies can be accomplished more slowly. The initial goal of therapy in urgency should be to achieve a DBP of 100 to 110 mm Hg. Excessive or rapid decreases in BP should be avoided to minimize the risk of cerebral hypoperfusion or coronary insufficiency. Normal BP can be attained gradually over several days as tolerated by the individual patient.

Aortic dissection

Acute, proximal aortic dissection (type A) is a surgical emergency, whereas uncomplicated, distal dissection (type B) can be treated successfully with medical therapy alone. All patients, including those treated surgically, require acute and chronic antihypertensive therapy to provide initial stabilization and to prevent complications (e.g., aortic rupture, continued dissection). Medical therapy of chronic stable

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aortic dissection should seek to maintain SBP at or below 130 to 140 mm Hg if tolerated. Antihypertensive agents with negative inotropic properties, including calcium channel antagonists, β-adrenergic antagonists, methyldopa, clonidine, and reserpine, are preferred for management in the postacute phase.

Sodium nitroprusside is considered the initial drug of choice because of the predictability of response and absence of tachyphylaxis. The dose should be titrated to achieve an SBP of 100 to 120 mm Hg or the lowest possible BP that permits adequate organ perfusion. Nitroprusside alone causes an increase in left ventricular contractility and subsequent arterial shearing forces, which contribute to ongoing intimal dissection. Thus, when using sodium nitroprusside, adequate simultaneous β-adrenergic antagonist therapy is essential, regardless of whether systolic hypertension is present. Traditionally, propranolol has been recommended. Esmolol, a cardioselective IV β-adrenergic antagonist with a very short duration of action, may be preferable, especially in patients with relative contraindications to β-antagonists. If esmolol is tolerated, a longer-acting β-adrenergic antagonist should be used.

IV labetalol has been used successfully as a single agent in the treatment of acute aortic dissection. Labetalol produces a dose-related decrease in BP and lowers contractility. It has the advantage of allowing for oral administration after the acute stage of dissection has been managed successfully.

Trimethaphan camsylate, a ganglionic blocking agent, can be used as a single IV agent if sodium nitroprusside or β-adrenergic antagonists cannot be tolerated. Unlike sodium nitroprusside, trimethaphan reduces left ventricular contractility. Because trimethaphan is associated with rapid tachyphylaxis and sympathalgia (e.g., orthostatic hypotension, blurred vision, and urinary retention), other drugs are preferable.

Individual patient considerations. Cultural and other individual differences among patients must be considered in planning a therapeutic regimen. Although classification of adult BP is somewhat arbitrary, it may nevertheless be useful in making clinical decisions (Table 4).

The elderly hypertensive patient (older than 60 years) is generally characterized by increased vascular resistance, decreased plasma renin activity, and greater LVH than in younger patients. Often elderly hypertensive patients have coexisting medical problems that must be considered in initiating antihypertensive therapy. Drug doses should be increased slowly to avoid adverse effects and hypotension. Diuretics as initial therapy have been shown to decrease the incidence of stroke, fatal MI, and overall mortality in this age group (JAMA 1991;265:3255-3264). Calcium channel antagonists decrease vascular resistance, have no adverse effects on lipid levels, and are also good choices for elderly patients. ACE inhibitors and ARBs may be effective agents in this population.

Black hypertensive patients generally have a lower plasma renin level, higher plasma volume, and higher vascular resistance than do white patients. Thus, black patients respond well to diuretics, alone or in combination with calcium channel antagonists. ACE inhibitors, ARBs, and β-adrenergic antagonists are also effective agents in this population particularly when combined with a diuretic.

The obese hypertensive patient is characterized by more modest elevations in vascular resistance, higher cardiac output, expanded intravascular volume, and lower plasma renin activity at any given level of arterial pressure. Weight reduction is the primary goal of therapy and is effective in reducing BP and causing regression of LVH.

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The diabetic patient with nephropathy may have significant proteinuria and renal insufficiency, which can complicate management (see Chapter 10, Renal Diseases). Control of BP is the most important intervention shown to slow loss of renal function. ACE inhibitors should be used as first-line therapy, as they have been shown to decrease proteinuria and to slow progressive loss of renal function independent of their antihypertensive effects. ACE inhibitors may also be beneficial in reducing the rates of death, MI, and stroke in diabetics who have cardiovascular risk factors but lack left ventricular dysfunction. Hyperkalemia is a common side effect in diabetic patients treated with ACE inhibitors, especially in those with moderate to severe impairment of their GFR. ARBs are also effective antihypertensive agents and have been shown to slow the rate of progression to end-stage renal disease, thus supporting a renal protective effect (N Engl J Med 2001 Sep 20;345(12):861-869).

The hypertensive patient with chronic renal insufficiency has hypertension that usually is partially volume dependent. Retention of sodium and water exacerbates the existing hypertensive state, and diuretics are important in the management of this problem. With a serum creatinine > 2.5 mg/dL, loop diuretics are the most effective class.

The hypertensive patient with LVH is at increased risk for sudden death, MI, and all-cause mortality. Although there is no direct evidence, regression of LVH could be expected to reduce the risk for subsequent complications. ACE inhibitors appear to have the greatest effect on regression.

The hypertensive patient with CAD is at increased risk for UA and MI. β-Adrenergic antagonists can be used as first-line agents in these patients as they can

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decrease cardiac mortality and subsequent reinfarction in the setting of acute MI and can decrease progression to MI in those who present with UA. β-Adrenergic antagonists also have a role in secondary prevention of cardiac events and in increasing long-term survival after MI. Care should be exercised in those with cardiac conduction system disease. Calcium channel antagonists should be used with caution in the setting of acute MI, as studies have shown conflicting results from their use. ACE inhibitors are also useful in patients with CAD and decrease mortality in individuals who present with acute MI, especially those with left ventricular dysfunction, and more recently have been shown to decrease mortality in patients without left ventricular dysfunction.

The hypertensive patient with HF is at risk for progressive left ventricular dilatation and sudden death. In this population, ACE inhibitors decrease mortality (N Engl J Med 1992;327:685-691), and in the setting of acute MI, they decrease the risk of recurrent MI, hospitalization for HF, and mortality (N Engl J Med 1992;327:669-677). ARBs have similar beneficial effects, and they appear to be an effective alternative in patients who are unable to tolerate an ACE inhibitor (N Engl J Med 2001;345:1667-1675). Nitrates and hydralazine also decrease mortality in patients with HF irrespective of hypertension, but hydralazine can cause reflex tachycardia and worsening ischemia in patients with unstable coronary syndromes and should be used with caution. Calcium channel antagonists should generally be avoided in patients in whom negative inotropic effects would affect their status adversely.

Pregnancy and hypertension

Hypertension in the setting of pregnancy is a special situation because of the potential for maternal and fetal morbidity and mortality associated with elevated BP and the clinical syndromes of preeclampsia and eclampsia. The possibility of teratogenic or other adverse effects of antihypertensive medications on fetal development also should be considered.

Classification of hypertension during pregnancy has been proposed by the American College of Obstetrics and Gynecology (N Engl J Med 1996;335:257-265).

Preeclampsia or eclampsia. Preeclampsia is a condition defined by pregnancy, hypertension, proteinuria, generalized edema, and, occasionally coagulation and liver function abnormalities after 20 weeks gestation. Eclampsia encompasses these parameters in addition to generalized seizures.

Chronic hypertension. This disorder is defined by a BP > 140/90 mm Hg before the 20th week of pregnancy.

Transient hypertension. This condition results in increases in BP without associated proteinuria or CNS manifestations. BP returns to normal within 10 days of delivery.

Therapy. Treatment of hypertension in pregnancy should begin if the DBP is >100 mm Hg.

Nonpharmacologic therapy, such as weight reduction and vigorous exercise, is not recommended during pregnancy.

Alcohol and tobacco use should be strongly discouraged.

Pharmacologic intervention with methyldopa is recommended as first-line therapy because of its proven safety. Hydralazine and labetalol are also safe and can be used as alternative agents; both can be used parenterally.

Other antihypertensives have theoretical disadvantages, but none except the ACE inhibitors have been proven to increase fetal morbidity or mortality.

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If a patient is suspected of having preeclampsia or eclampsia, urgent referral to an obstetrician who specializes in high-risk pregnancy is recommended.

Monoamine oxidase inhibitors (MAOIs). MAOIs used in association with certain drugs or foods can produce a catecholamine excess state and accelerated hypertension. Interactions are common with tricyclic antidepressants, meperidine, methyldopa, levodopa, sympathomimetic agents, and antihistamines. Tyraminecontaining foods that can lead to this syndrome include certain cheeses, red wine, beer, chocolate, chicken liver, processed meat, herring, broad beans, canned figs, and yeast. Nitroprusside, labetalol, and phentolamine have been used effectively in the treatment of accelerated hypertension associated with monoamine oxidase inhibitor use (Table 3).

Table 4 Classification of Blood Pressure for Adults Aged 18 Years and Oldera

Category

Systolic Pressure (mm Hg)

Diastolic Pressure (mm Hg)

Normalb

<120 and

<80

Prehypertension

120-139 or

80-89

Hypertensionc

Stage 1

140-159 or

90-99

Stage 2

>160 or

>100

Isolated systolic hypertension is defined as a systolic BP of 140 mm Hg or more and a diastolic BP of <90 mm Hg and staged appropriately (e.g., 170/85 mm Hg is defined as stage 2 isolated systolic hypertension). In addition to classifying stages of hypertension on the basis of average BP levels, the clinician should specify the presence or absence of target organ disease and additional risk factors. This specificity is important for risk classification and management.

aNot taking antihypertensive drugs and not acutely ill. When systolic and diastolic pressures fall into different categories, the higher category should be selected to classify the individual's blood pressure (BP) status.

b Optimal BP with respect to cardiovascular risk is <120 mm Hg systolic and <80 mm Hg diastolic. However, unusually low readings should be evaluated for clinical significance.

c Based on the average of two or more readings taken at each of two or more visits after an initial screening.

From The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. Chobanian AV, Bakris GL, Black HR, et al.; National Heart, Lung, and Blood Institute Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; National High Blood Pressure Education Program Coordinating Committee. JAMA 2003 May 21;289(19):2560-2572. Epub 2003 May 14. Erratum in: JAMA 2003 Jul 9;290(2):197, with permission.

COMPLICATIONS

Withdrawal syndrome associated with discontinuation of antihypertensive therapy. In substituting therapy in patients with moderate to severe hypertension, it is reasonable to increase doses of the new medication in small increments while tapering the previous medication to avoid excessive BP fluctuations. On occasion, an AWS develops, usually within the first 24 to 72 hours. Occasionally BP rises to levels that are much higher than those of baseline values. The most severe complications of AWS include encephalopathy, stroke, MI, and sudden death. The AWS is associated most commonly with centrally acting adrenergic agents (particularly clonidine) and β-adrenergic antagonists but has been reported with other agents as well including diuretics. Rarely should BP medications be withdrawn; rather, in discontinuing therapy these drugs should be tapered over several days to weeks unless other medications are used to substitute in the interim. Discontinuation of antihypertensive medications should be done with caution in patients with preexisting cerebrovascular or cardiac disease. Management of AWS by reinstitution of the previously administered drug is generally effective. Sodium nitroprusside (Table 2) is the treatment of choice when parenteral administration of an antihypertensive agent is required or when the identity of the previously administered agent is unknown. In the AWS caused by clonidine, β-adrenergic antagonists should not be used because unopposed α-adrenergic activity will be augmented and may exacerbate hypertension. However, labetalol (Table 2) may be useful in this situation.

PATIENT EDUCATION

Patient education is an essential component of the treatment plan and promotes patient compliance. Physicians should emphasize that:

Lifelong treatment is usually required.

Symptoms are an unreliable gauge of severity of hypertension.

Prognosis improves with proper management.

Lifestyle modifications are essential.

MONITORING/FOLLOW-UP

BP measurements should be performed on multiple occasions under nonstressful circumstances (e.g., rest, sitting, empty bladder, comfortable temperature) to obtain an accurate assessment of BP in a given patient.

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Hypertension should not be diagnosed on the basis of one measurement alone, unless it is >210/120 mm Hg or accompanied by target organ damage. Two or more abnormal readings should be obtained, preferably over a period of several weeks, before therapy is considered.

Care should also be used to exclude pseudohypertension, which usually occurs in elderly individuals with stiff, noncompressible vessels. A palpable artery that persists after cuff inflation (Osler sign) should alert the physician to this possibility.

Home and ambulatory BP monitoring can be used to assess a patient's true average BP, which correlates better with target organ damage. Circumstances in which ambulatory BP monitoring might be of value include:

Suspected “white-coat hypertension” (increases in BP associated with the stress of physician office visits) should be evaluated carefully.

Evaluation of possible “drug resistance” where suspected.

Dyslipidemia

GENERAL PRINCIPLES

Lipids are sparingly soluble molecules that include cholesterol, fatty acids, and their derivatives.

Plasma lipids are transported by lipoprotein particles composed of proteins called apolipoproteins, and phospholipids, cholesterol esters, and triglycerides.

Human plasma lipoproteins are separated into five major classes based on density:

Chylomicrons (least dense)

Very-low-density lipoproteins (VLDLs)

Intermediate-density lipoproteins (IDLs)

Low-density lipoproteins (LDLs)

High-density lipoproteins (HDLs)

A sixth class, lipoprotein(a) [Lp(a)], resembles LDL in lipid composition and has a density that overlaps LDL and HDL

Physical properties of plasma lipoproteins are summarized in Table 5.

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Atherosclerosis and lipoproteins. Nearly 90% of patients with coronary heart disease (CHD) have some form of dyslipidemia. Increased levels of LDL, remnant lipoproteins, and Lp(a) as well as decreased levels of HDL have all been associated with an increased risk of premature vascular disease (J Am Coll Cardiol 1992;19:792-802; Circulation 1998;97:2519-2526).

Clinical dyslipoproteinemias

Most dyslipidemias are multifactorial in etiology and reflect the effects of uncharacterized genetic influences coupled with diet, activity, smoking, alcohol use, and comorbid conditions such as obesity and DM.

Differential diagnosis of the major lipid abnormalities is summarized in Table 6.

The major genetic dyslipoproteinemias are reviewed in Table 7 (Circulation 1974; 49:476-488; J Lipid Res 1990;31:1337-1349; Clin Invest 1993;71:362-366).

Standards of care for hyperlipidemia

LDL cholesterol-lowering therapy, particularly with hydroxymethylglutarylcoenzyme A (HMG-CoA) reductase inhibitors, lowers the risk of CHDrelated death, morbidity, and revascularization procedures in hypercholesterolemic patients with (secondary prevention) (Lancet 1994;344:1383-1389; N Engl J Med 1996;335:1001-1009; N Engl J Med 1998;339:1349-1357; Lancet 2002;360:7-22) or without (primary prevention) known CHD (Lancet 2002;360:7-22; N Engl J Med 1995;333:1301-1307; JAMA 1998;279:1615-1622; Lancet 2003;361: 1149-1158; Lancet 2004;364:685-696).

Identification and management of high LDL cholesterol is the primary goal of the National Cholesterol Education Program's (NCEP's) third expert report on cholesterol management in adults, or Adult Treatment Program III (ATP III) (JAMA 2001;285:2486-2497).

The ATP III executive summary and full report can be viewed online at www. nhlbi.nih.gov/guidelines/cholesterol/.

Table 5 Physical Properties of Plasma Lipoproteins

Lipoprotein

Lipid Composition

Origin

Apolipoproteins

Chylomicrons

TG, 90%; chol, 3%

Intestine

B-48; C-I, C-II, C-III; E

VLDL

TG, 55%; chol, 20%

Liver

B-100; C-I, C-II, C-III; E

IDL

TG, 30%; chol, 35%

Metabolic product of VLDL

B-100; C-I, C-II, C-III; E

LDL

TG, 10%; chol, 50%

Metabolic product of IDL

B-100

HDL

TG, 5%; chol, 20%

Liver, intestine

A-I, A-II, A-IV; C-I, C-II, C-III; E

Lp(a)

TG, 10%; chol, 50%

Liver

B-100; Apo(a)

Chol, cholesterol; HDL, high-density lipoprotein; IDL, intermediate-density lipoprotein; LDL, low-density lipoprotein; Lp(a), lipoprotein(a); TG, triglyceride; VLDL, very-low-density lipoprotein.

aBalance of particle composition: protein and phospholipid.

Table 6 Differential Diagnosis of Major Lipid Abnormalities

Lipid Abnormality

Primary Disorders

Secondary Disorders

Hypercholesterolemia

Polygenic, familial hypercholesterolemia, familial defective apo B-100

Hypothyroidism, nephrotic syndrome

Hypertriglyceridemia

Lipoprotein lipase deficiency, apo C-II deficiency, familial hypertriglyceridemia

Diabetes mellitus, obesity, metabolic syndrome, alcohol use, oral estrogen

Combined hyperlipidemia

Familial combined hyperlipidemia, type III hyperlipoproteinemia

Diabetes mellitus, obesity, metabolic syndrome, hypothyroidism, nephrotic syndrome

Low HDL

Familial alpha lipoproteinemia, Tangier disease, familial HDL deficiency, lecithin:cholesterol acyltransferase deficiency

Diabetes mellitus, metabolic syndrome, hypertriglyceridemia, smoking

HDL, high-density lipoprotein.

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Table 7 Review of Major Genetic Dyslipoproteinemias

Type of Genetic Dyslipidemia

Typical Lipid Profile

Type of Inheritance

Phenotypic Features

Other Information

Familial hypercholesterolemia (FH)

Increased total (>300 mg/dL) and LDL (>250 mg/dL) cholesterol

Homozygous form (rare) can have total cholesterol

>600 mg/dL and LDL

>550 mg/dL

Autosomal dominant

Premature CAD

Tendon xanthomas

Xanthelasmata

Premature arcus corneae

Due to mutations of the LDL receptor that lead to defective uptake and degradation of LDL

Familial combined hyperlipidemia (FCH)

High levels of VLDL, LDL, or both

LDL apo B-100 level >130 mg/dL

Autosomal dominant

Premature CAD

Patients do not develop tendon xanthomas

Genetic and metabolic defects are not established

Familial defective apolipoprotein B-100

Similar to familial hypercholesterolemia

Similar to familial hypercholesterolemia

Most all cases are due to a glutamine for arginine mutation at amino acid 3500 of apo B-100

Type III hyperlipoproteinemia (familial dysbetalipoproteinemia)

Symmetric elevations of cholesterol and triglycerides (300-500 mg/dL)

Elevated VLDL to triglyceride ratio (>0.3)

Autosomal recessive

Premature CAD

Tuberous or tuberoeruptive xanthomas

Planar xanthomas of the palmar creases are essentially pathognomonic

Many homozygotes are normolipidemic and emergence of hyperlipidemia often requires a secondary metabolic factor such as diabetes mellitus, hypothyroidism, or obesity

Chylomicronemia syndrome

Most patients have triglycerides in the range of 150-500 mg/dL

Clinical manifestations occur when triglycerides exceed 1,500 mg/dL

Onset before puberty indicates deficiency of lipoprotein lipase or apo C-II, both autosomal recessive

Familial hypertriglyceridemia is an autosomal dominant disorder caused by overproduction of VLDL triglycerides and manifests in adults

Eruptive xanthomas

Lipemia retinalis

Pancreatitis

Hepatosplenomegaly

Familial hypertriglyceridemia and FCH patients may develop chylomicronemia syndrome in the presence of secondary factors such as obesity, alcohol use, or diabetes

CAD, coronary artery disease; LDL, low-density lipoprotein, VLDL, very-low-density lipoprotein.

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DIAGNOSIS

Screening

Screening for hypercholesterolemia should begin in all adults aged 20 years or older.

Screening is best performed with a lipid profile (total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides) obtained after a 12-hour fast.

If a fasting lipid panel cannot be obtained, total and HDL cholesterol should be measured.

Measurement of fasting lipids is indicated if the total cholesterol is ≥200 mg/dL or HDL cholesterol is ≤40 mg/dL.

If lipids are unremarkable and the patient has no major risk factors for CHD (Table 8), then screening can be performed every 5 years (JAMA 2001;285:2486-2497).

Patients hospitalized for an acute coronary syndrome (ACS) or coronary revascularization should have a lipid panel obtained within 24 hours of admission if lipid levels are unknown.

Individuals with hyperlipidemia should be evaluated for potential secondary causes, including hypothyroidism, DM, obstructive liver disease, chronic renal disease, or nephrotic syndrome, or medications such as estrogens, progestins, anabolic steroids, and corticosteroids.

TREATMENT

Therapeutic lifestyle change

ATP III thresholds for initiating cholesterol-lowering therapy with therapeutic lifestyle change (TLC, diet and exercise) and hypolipidemic drugs are summarized in Table 9 (Circulation 2004;110:227-239).

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All patients requiring cholesterol treatment should implement a diet restricted in total and saturated fat intake in accordance with ATP III recommendations (Table 10) (JAMA 2001;285:2486-2497).

Moderate exercise and weight reduction is also recommended.

A registered dietitian may be helpful to plan and start a saturated fat-restricted and weight loss-promoting diet.

Treatment targets

High risk and very high risk

The ATP III LDL cholesterol treatment target for all high-risk patients is <100 mg/dL (JAMA 2001;285:2486-2497).

For CHD patients in the very-high-risk category, an LDL cholesterol <70 mg/dL is a therapeutic option (Circulation 2004;110:227-239).

An LDL cholesterol of ≥100 mg/dL is now identified as the threshold for simultaneous treatment with TLC and lipid-lowering agents (Circulation 2004;110:227-239).

Based on outcomes in the Heart Protection Study (HPS), lipid-lowering drug therapy is also an option for patients with CHD and baseline LDL cholesterol < 100 mg/dL (Lancet 2002;360:7-22).

If a high-risk patient has hypertriglyceridemia or low HDL cholesterol, a fibrate or nicotinic acid (niacin) may be added to cholesterol-lowering therapy (Circulation 2004;110:227-239).

Moderately high risk

Patients with two or more non-LDL cholesterol risk factors and a Framingham point score predicting a 10-year CHD risk of 10% to 20% are considered at moderately high risk of CHD.

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Pharmacotherapy should be initiated if LDL cholesterol is ≥130 mg/dL.

ATP III identifies an LDL cholesterol target < 100 mg/dL as optional for this group, with drug therapy to be considered for patients with baseline LDL cholesterol 100 to 129 mg/dL.

Patients with two or more risk factors and a 10-year risk <10% are candidates for drug therapy when LDL cholesterol remains ≥160 mg/dL despite TLC (Circulation 2004;110:227-239).

Low risk

For low-risk patients (0 to 1 risk factors), cholesterol-lowering therapy should be considered if the LDL cholesterol is ≥190 mg/dL, especially for patients who have undergone a 3-month trial of TLC.

Patients with very high LDL concentrations (≥190 mg/dL) often have a hereditary dyslipidemia and require treatment with multiple lipid-lowering agents. These patients should be referred to a lipid specialist, and family members should be screened with a fasting lipid battery.

When LDL cholesterol is 160 to 189 mg/dL, drug therapy should be considered if the patient has a significant risk factor for cardiovascular disease, such as heavy tobacco use, poorly controlled hypertension, strong family history of early CHD, or low HDL cholesterol (Circulation 2004;110:227-239).

Assessing response to therapy

Response to therapy should be assessed after 6 weeks and the dose of medication titrated if the LDL cholesterol treatment target is not achieved.

The initial dose of a cholesterol-lowering drug should be sufficient to achieve a 30% to 40% reduction in LDL cholesterol.

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If target LDL cholesterol has not been reached after 12 weeks, current therapy should be intensified by further dose titration, adding another lipid-lowering agent, or referral to a lipid specialist.

Patients at goal should be monitored every 4 to 6 months.

Metabolic syndrome

The constellation of abdominal obesity, hypertension, glucose intolerance, and an atherogenic lipid profile (hypertriglyceridemia; low HDL cholesterol; and small, dense LDL cholesterol) characterizes a condition called the metabolic syndrome. ATP III diagnostic criteria for the metabolic syndrome are summarized in Table 11 (JAMA 2001;285:2486-2497; http://www.idf.org/home/index. cfm?node=1429).

Approximately 22% of Americans qualify for a diagnosis of the metabolic syndrome by ATP III criteria. Prevalence is increased in older individuals, women, Hispanic Americans, and African Americans (JAMA 2002;287:356-359).

Multiple studies have demonstrated an association between cardiovascular events and death and all-cause mortality with the metabolic syndrome (Am J Med 2006; 119:812-819).

ATP III recognizes the metabolic syndrome as a secondary treatment target after LDL cholesterol is controlled (JAMA 2001;285:2486-2497).

The report recommends treating the underlying causes of metabolic syndrome (overweight/obesity, physical inactivity) by implementing weight loss and aerobic exercise and managing cardiovascular risks, such as hypertension, that may persist despite lifestyle changes (JAMA 2001;285:2486-2497).

Hypertriglyceridemia

Recent analyses suggest that hypertriglyceridemia is an independent cardiovascular risk factor (Circulation 2007;115:450-458; Ann Intern Med 2007;147:377-385).

Hypertriglyceridemia is often observed in the metabolic syndrome, and there are many potential etiologies for hypertriglyceridemia, including obesity, DM, renal

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insufficiency, genetic dyslipidemias, and therapy with oral estrogen, glucocorticoids, or β-blockers.

The ATP III classification of serum triglyceride levels is as follows (JAMA 2001; 285:2486-2497):

Normal: <150 mg/dL

Borderline-high: 150 to 199 mg/dL

High: 200 to 499 mg/dL

Very high: ≥500 mg/dL

Treatment of hypertriglyceridemia depends on the degree of severity.

For patients with very high triglycerides, triglyceride reduction through a very low fat diet (≤15% of calories), exercise, weight loss, and drugs (fibrates, niacin) is the primary goal of therapy to prevent acute pancreatitis.

When patients have a lesser degree of hypertriglyceridemia, control of LDL cholesterol is the primary aim of initial therapy. TLC is emphasized as the initial intervention to lower triglycerides (JAMA 2001;285:2486-2497).

Non-HDL cholesterol

Non-HDL cholesterol is a secondary treatment target.

A patient's non-HDL cholesterol is calculated by subtracting HDL cholesterol from total cholesterol.

Target non-HDL cholesterol is 30 mg/dL higher than the LDL cholesterol target.

LDL and non-HDL cholesterol treatment targets for various degrees of cardiovascular risk are summarized in Table 12 (JAMA 2001;285:2486-2497; Circulation 2004;110:227-239).

Low HDL cholesterol

One of the modifications from ATP II includes redefining low HDL cholesterol as <40 mg/dL.

Low HDL cholesterol is an independent CHD risk factor that is identified as a non-LDL cholesterol risk and included as a component of the Framingham scoring algorithm (JAMA 1986;256:2835-2838).

Etiologies for low HDL cholesterol include physical inactivity, obesity, insulin resistance, DM, hypertriglyceridemia, cigarette smoking, high-carbohydrate diets (>60% calories), and certain medications (β-blockers, anabolic steroids, progestins).

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Because therapeutic interventions for low HDL cholesterol are of limited efficacy, ATP III identifies LDL cholesterol as the primary target of therapy for patients with low HDL cholesterol.

Low HDL cholesterol often occurs in the setting of hypertriglyceridemia and metabolic syndrome. Management of these conditions may result in improvement of HDL cholesterol.

Aerobic exercise, weight loss, smoking cessation, menopausal estrogen replacement, and treatment with niacin or fibrates may elevate low HDL cholesterol (JAMA 2001;285:2486-2497).

Lipid-lowering therapy and age

The risk of a fatal or nonfatal cardiovascular event increases with age, and most cardiovascular events occur in patients aged 65 years and older.

Secondary prevention trials with the HMG-CoA reductase inhibitors have demonstrated significant clinical benefit for patients aged 65 to 75 years.

The HPS failed to show an age threshold for primary or secondary prevention with statin therapy. Patients aged 75 to 80 years at study entry experienced a nearly 30% reduction in major vascular events (Lancet 2002;360:7-22).

The Prospective Study of Pravastatin in the Elderly (PROSPER) trial found a significant reduction in major coronary events among patients aged 70 to 82 years with vascular disease or CHD risks treated with pravastatin (Lancet 2002;360:1623-1630).

ATP III does not place age restrictions on treatment of hypercholesterolemia in elderly adults.

ATP III recommends TLC for young adults (men aged 20 to 35 years; women aged 20 to 45 years) with an LDL level ≥ 130 mg/dL. Drug therapy should be considered in the following high-risk groups:

Men who both smoke and have elevated LDL levels (160 to 189 mg/dL).

All young adults with an LDL ≥ 190 mg/dL.

Those with an inherited dyslipidemia (JAMA 2001;285:2486-2497).

Treatment of elevated LDL cholesterol

HMG-CoA reductase inhibitors (statins)

Statins (Table 13) are the treatment of choice for elevated LDL cholesterol (JAMA 2001;285:2486-2497; N Engl J Med 1999;341:498-511; Ann Pharmacother 2002;36:1907-1917; Circulation 2002;106:1024-1028; JAMA 1984;251:351-364).

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The lipid-lowering effect of statins appears within the first week of use and becomes stable after approximately 4 weeks of use.

Common side effects (5% to 10% of patients) include GI upset (e.g., abdominal pain, diarrhea, bloating, constipation), and muscle pain or weakness, which can occur without creatinine kinase elevations. Other potential side effects include malaise, fatigue, headache, and rash (N Engl J Med 1999;341:498-511; JAMA 1984;251:351-364).

Elevations of liver transaminases two to three times the upper limit of normal are dose dependent and reversible with discontinuation of the drug.

- Liver enzymes should be measured before initiating therapy, at 8 to 12 weeks after dose initiation or titration, then every 6 months.

- The medication should be discontinued if liver transaminases elevate to more than three times the upper limit of normal (Circulation 2002;106:1024-1028).

Because some of the statins undergo metabolism by the cytochrome P450 enzyme system, taking them in combination with other drugs metabolized by this enzyme system increases the risk of rhabdomyolysis (N Engl J Med 1999;341:498-511; Circulation 2002;106:1024-1028).

- Among these drugs are fibrates (greater risk with gemfibrozil), itraconazole, ketoconazole, erythromycin, clarithromycin, cyclosporin, nefazodone, and protease inhibitors (Circulation 2002;106:1024-1028).

- Statins may also interact with large quantities of grapefruit juice to increase the risk of myopathy, although the precise mechanism of this interaction is unclear.

- Simvastatin can increase levels of warfarin and digoxin. Rosuvastatin may also increase warfarin levels.

Bile acid sequestrant resins

Currently available bile acid sequestrant resins include the following:

- Cholestyramine: 4 to 24 g PO/d in divided doses before meals.

- Colestipol: tablets, 2 to 16 g PO/d; granules, 5 to 30 g PO/d in divided doses before meals.

- Colesevelam: 625-mg tablets; 3 tablets PO bid or 6 tablets PO daily with food (maximum, 7 tablets PO/d).

Bile acid sequestrants typically lower LDL levels by 15% to 30% and thereby lower the incidence of CHD (N Engl J Med 1999;341:498-511;JAMA 1984;251: 351-364). These agents should not be used as monotherapy in patients with triglyceride levels > 250 mg/dL because they can raise triglyceride levels. They may be combined with nicotinic acid or statins.

Common side effects of resins include constipation, abdominal pain, bloating, nausea, and flatulence.

Bile acid sequestrants may decrease oral absorption of many other drugs, including warfarin, digoxin, thyroid hormone, thiazide diuretics, amiodarone, glipizide, and statins.

- Colesevelam interacts with fewer drugs than the older resins.

- Other medications should be given 1 hour before or 4 hours after resins.

Nicotinic acid (Niacin)

Niacin can lower LDL cholesterol levels by ≥15%, lower triglyceride levels 20% to 50%, and raise HDL cholesterol levels by up to 35% (Circulation 2007;115:450-458; Arch Intern Med 1994;154:1586-1595).

Crystalline niacin is given 1 to 3 g PO/d in two to three divided doses with meals. Extended-release niacin is dosed at night. The starting dose is 500 mg PO, and

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the dose may be titrated monthly in 500-mg increments to a maximum of 2,000 mg PO (administer dose with milk or crackers).

Common side effects of niacin include flushing, pruritus, headache, nausea, and bloating. Other potential side effects include elevation of liver transaminases, hyperuricemia, and hyperglycemia.

- Flushing may be decreased with use of aspirin 30 minutes before the first few doses.

- Hepatotoxicity associated with niacin is partially dose dependent and appears to be more prevalent with over-the-counter time-release preparations.

Avoid use of niacin in patients with gout, liver disease, active peptic ulcer disease, and uncontrolled DM.

- Niacin can be used with care in patients with well-controlled DM (HgA1c ≤ 7%).

- Serum transaminases, glucose, and uric acid levels should be monitored every 6 to 8 weeks during dose titration, then every 4 months.

Ezetimibe

Ezetimibe is currently the only available cholesterol absorption inhibitor.

It appears to act at the brush border of the small intestine and inhibits cholesterol absorption.

The recommended dosing is 10 mg PO once daily. No dosage adjustment is required for renal insufficiency, mild hepatic impairment, or in elderly patients.

Ezetimibe may provide an additional 25% mean reduction in LDL when combined with a statin and provides an approximately 18% decrease in LDL when used as monotherapy (Am J Cardiol 2002;90:1092-1097; Eur Heart J 2003;24:729-741; Am J Cardiol 2002;90:1084-1091; Mayo Clin Proc 2004;79: 620-629).

It is not recommended for use in patients with moderate to severe hepatic impairment.

There appear to be few side effects associated with ezetimibe.

- In clinical trials, there was no excess of rhabdomyolysis or myopathy when compared with statin or placebo alone.

- There is a low incidence of diarrhea and abdominal pain compared to placebo. Liver function monitoring is not required with monotherapy because there appears to be no significant impact on liver enzymes when this drug is used alone.

- Liver enzymes should be monitored when used in conjunction with a statin, as there appears to be a slight increased incidence of enzyme elevations with combination therapy.

Long-term clinical outcome trials of ezetimibe are ongoing. There has been one short-term surrogate outcome trial suggesting a lack of additive effectiveness with regard to carotid intima-media thickness (N Engl J Med 2008;358:1431-1443). The clinical utility of these results has been questioned and the matter is currently unresolved.

Treatment of hypertriglyceridemia

Nonpharmacologic treatment

Nonpharmacologic treatments are important in the therapy of hypertriglyceridemia.

Nonpharmacologic approaches include the following:

- Changing oral estrogen replacement to transdermal estrogen

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- Decreasing alcohol intake

- Encouraging weight loss and exercise

- Controlling hyperglycemia in patients with DM

- Avoiding simple sugars and very high carbohydrate diets

Pharmacologic treatment

Pharmacologic treatment of isolated hypertriglyceridemia consists of a fibric acid derivative or niacin.

Statins may be effective for patients with mild to moderate hypertriglyceridemia and concomitant LDL cholesterol elevation (N Engl J Med 2007;357:1009-1017).

Fibric acid derivatives

- Currently available fibric acid derivatives include Gemfibrozil: 600 mg PO bid before meals; Fenofibrate: typically 48 to 145 mg PO/d.

- Fibrates generally lower triglyceride levels 30% to 50% and increase HDL levels 10% to 35%. They can lower LDL levels by 5% to 25% in patients with normal triglyceride levels, but may actually increase LDL levels in patients with elevated triglyceride levels.

- Common side effects include dyspepsia, abdominal pain, cholelithiasis, rash, and pruritus. Fibrates may potentiate the effects of warfarin (N Engl J Med 1999;341:498-511).

- Gemfibrozil given in conjunction with statins may increase the risk of rhabdomyolysis (Circulation 2002;106:1024-1028; Am J Med 2004;116:408-416; Am J Cardiol 2004;94:935-938; Am J Cardiol 2005;95:120-122; Lancet 2005;366:1849-1861).

Omega-3 fatty acids

- Omega-3 fatty acids from fish oil can lower triglycerides in high doses (J Clin Invest 1984;74:82-89; J Lipid Res 1990;31:1549-1558).

- The active ingredients are eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).

- To lower triglyceride levels, 1 to 6 g of EPA plus DHA is needed daily.

- Main side effects are burping, bloating, and diarrhea.

- A prescription form of omega-3 acid fatty acids is available and is indicated for triglycerides over 500 mg/dL; four tablets contain about 3.6 g of omega-3 acid ethyl esters and can lower triglycerides by 30%.

- In practice, omega-3 fatty acids are being used as an adjunct to statin or other drugs in patients with moderately elevated triglyceride levels.

- The combination of omega-3 fatty acids plus statin has the advantage of avoiding the risk of myopathy seen in the statin-fibrate combination (Am J Cardiol 2008;102:429-433; Am J Cardiol 2008;102:1040-1045).

Treatment of low HDL cholesterol

Low HDL cholesterol often occurs in the setting of hypertriglyceridemia and metabolic syndrome. Management of accompanying high LDL cholesterol, hypertriglyceridemia, and the metabolic syndrome may result in improvement of HDL cholesterol (Circulation 2001;104:3046-3051.)

Treatment specifically targeted at raising low HDL cholesterol levels may reduce the risk of cardiovascular events (JAMA 2007;298:786-798).

Nonpharmacologic therapies are the mainstay of treatment including:

Smoking cessation

Exercise

Weight loss

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In addition, medications known to lower HDL levels should be avoided such as β-blockers, progestins, and androgenic compounds.

Niacin is the most effective pharmacologic agent for increasing HDL levels (J Lipid Res 1990;31:1549-1558).

Table 8 Major Risk Factors That Modify LDL Goals

Cigarette smoking

Hypertension (blood pressure ≥ 140/90 mm Hg or on antihypertensive medication)

Low HDL cholesterol (<40 mg/dL)a

Family history of premature CHD (CHD in male first-degree relative <age 55 yr; CHD in female first-degree relative <age 65 yr)

Age (men ≥ 45 yr; women ≥ 55 yr)

CHD, coronary heart disease; HDL, high-density lipoprotein; LDL, low-density lipoprotein.

a HDL cholesterol ≥60 mg/dL counts as a “negative” risk factor; its presence removes one risk factor from the total count.

Modified from Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;285:2486-2497.

Table 9 ATP III Low-Density LDL-C Goals and Thresholds for Therapeutic Lifestyle Changes and Drug Therapy

Category

LDL-C Goal

Start TLC

Start Drug Therapy

Very high risk

<70 mg/dL

Any LDL-C

LDL-C ≥70 mg/dL

High risk

<100 mg/dL

≥100 mg/dL

≥100 mg/dL (consider if baseline LDL-C < 100 mg/dL)

Moderately high risk

< 130 mg/dL (<100 mg/dL optional)

≥130 mg/dL

≥130 mg/dL (optional if baseline LDL-C 100-129 mg/dL)

Moderate risk

<130 mg/dL

≥130 mg/dL

≥160 mg/dL

Lower risk

<160 mg/dL

≥160 mg/dL

≥190 mg/dL (optional if baseline LDL-C 160-189 mg/dL)

ATP III, Adult Treatment Panel III; LDL-C, low-density lipoprotein cholesterol; TLC, therapeutic lifestyle changes.

Modified from Grundy SM, Cleeman C, Merz NB, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. Circulation 2004;110:227-239.

Table 10 Nutrient Composition of the Therapeutic Lifestyle Change Diet

Nutrient

Recommended Intake

Saturated fata

<7% of total calories

Polyunsaturated fat

Up to 10% of total calories

Monounsaturated fat

Up to 20% of total calories

Total fat

25-35% of total calories

Carbohydrateb

50-60% of total calories

Fiber

20-30 g/d

Protein

Approximately 15% of total calories

Cholesterol

<200 mg/d

Total calories (energy)c

Balance energy intake and expenditure to maintain desirable body weight/prevent weight gain

a Trans fatty acids are another low-density lipoprotein (LDL)-raising fat that should be kept at a low intake.

b Carbohydrate should be derived predominantly from foods rich in complex carbohydrates, including grains (especially whole grains), fruits, and vegetables.

c Daily energy expenditure should include at least moderate physical activity (contributing approximately 200 kcal/d).

From Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;285:2486-2497, with permission.

Table 11 ATP III Diagnostic Criteria for the Metabolic Syndrome

Risk Factor

ATP IIIa Definition

Carbohydrate metabolism

Fasting glucose ≥ 110 mg/dL (alternatively >100 mg/dL)

Abdominal obesityb

Men, waist > 40 in.

Women, waist > 35 in.

Dyslipidemia

Triglycerides ≥ 150 mg/dL

Men, HDL cholesterol < 40 mg/dL

Women, HDL cholesterol < 50 mg/dL

Hypertension

BP ≥ 130/85 mm Hg

ATP III, Adult Treatment Panel III; BP, blood pressure; HDL, high-density lipoprotein.

a To qualify for the diagnosis of metabolic syndrome by ATP III criteria, a patient must meet at least three of the five criteria (hyperglycemia, abdominal obesity, high triglycerides, low HDL cholesterol, high blood pressure).

b Waist circumferences in Asian and South Asian patients may require different cutpoints.

Modified from Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;285:2486-2497.

Table 12 Comparison of LDL-C and Non-HDL-C Goals by CHD Risk Category

Category

LDL-C Target (mg/dL)

Non-HDL-C Target (mg/dL)

Very high risk

<70

<100

High risk

<100

<130

Moderately high risk

<130

<160

Moderate risk

<130

<160

Low risk

<160

<190

CHD, coronary heart disease; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol.

Modified from Grundy SM, Cleeman C, Merz NB, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. Circulation 2004;110:227-239.

Table 13 Currently Available Statins

Name

Atorvastatin

Fluvastatin

Lovastatin

Pravastatin

Rosuvastatin

Simvastatin

Dose range (mg PO/d)

10-80

20-80

10-80

10-80

5-40

10-80

Triglyceride effect (%)

↓ 13-32

↓ 5-35

↓ 2-13

↓ 3-15

↓ 10-35

↓ 12-36

LDL effect (%)

↓ 38-54

↓ 17-36

↓ 29-8

↓ 19-34

↓ 41—65

↓ 28-46

HDL effect (%)

↑ 4.8-5.5

↑ 0.9-12

↑ 4.6-8

↑ 3-9.9

↑ 10-14

↑ 5.2-10

HDL, high-density lipoprotein; LDL, low-density lipoprotein; ↑, increased; ↓, decreased.

Table 14 ATP III Categories of CHD Risk

Category

Definition

Very high risk

CHD and:

Multiple risk factors (especially diabetes)

Severe and poorly controlled risk factors (especially continued cigarette smoking)

Multiple risk factors of the metabolic syndrome

Acute coronary syndromes

High risk

CHD or CHD risk equivalent

Moderately high risk

2+ risk factors and 10-yr CHD risk 10-20%

Moderate risk

2+ risk factors and 10-yr CHD risk <10%

Lower risk

0-1 risk factors

ATP III, Adult Treatment Panel III; CHD, coronary heart disease.

Modified from Grundy SM, Cleeman C, Merz NB, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. Circulation 2004;110:227.

Lifestyle/Risk Modification

Risk assessment

A major innovation of ATP III is a formal method of CHD risk assessment. ATP III now recognizes five categories of CHD risk: very high, high, moderately high, moderate, and lower risk. These CHD risk categories are defined in Table 14.

DM, noncoronary atherosclerosis (symptomatic cerebrovascular disease, peripheral artery disease, abdominal aortic aneurysm), or multiple risk factors conferring a 10-year CHD risk of more than 20% are considered CHD risk equivalents in ATP III (Circulation 2004;110:227-239).

Risk assessment for patients without known CHD or CHD risk equivalents begins with consideration of five risk factors summarized in Table 8 (JAMA 2001;285:2486-2497).

A Framingham point score should be determined for any individual with two or more non-LDL cholesterol risk factors. Framingham point score algorithms for men and women are summarized in Table 15 (JAMA 2001;285:2486-2497; Circulation 2004;110:227-239; Circulation 1998;97:1837-1847).

Patients with multiple non-LDL cholesterol CHD risk factors are then divided into those with a 10-year CHD risk >20%, 10% to 20%, or <10%.

Presently, emerging risk factors (e.g., obesity, sedentary lifestyle, prothrombotic and proinflammatory factors, and impaired fasting glucose) do not impact risk assessment, although they may influence clinical judgment when determining therapeutic options.

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Table 15 Estimate of 10-Year risk (Framingham Point Scores) for Men and Women

Estimate of 10-yr Risk for Men

Age (yr)

Points

20-34

-9

35-39

-4

40-44

0

45-49

3

50-54

6

55-59

8

60-64

10

65-69

11

70-74

12

75-79

13

Points

Total

Cholesterol

Age 20-39

Age 40-49

Age 50-59

Age 60-69

Age 70-79

<160

0

0

0

0

0

160-199

4

3

2

1

0

200-239

7

5

3

1

0

240-279

9

6

4

2

1

≥280

11

8

5

3

1

Points

Age 20-39

Age 40-49

Age 50-59

Age 60-69

Age 70-79

Nonsmoker

0

0

0

0

0

Smoker

8

5

3

1

1

HDL (mg/dL)

Points

Systolic BP (mm Hg)

Points if Untreated

Points if Treated

≥60

-1

<120

0

0

50-59

0

120-129

0

1

40-49

1

130-139

1

2

<40

2

140-159

1

2

≥160

2

3

Point Total

10-yr Risk (%)

Point total

10-yr Risk (%)

<0

<1

9

5

0

1

10

6

1

1

11

8

2

1

12

10

3

1

13

12

4

1

14

16

5

2

15

20

6

2

16

25

7

3

≥17

≥30

8

4

Estimate of 10-yr Risk for Men

Age (yr)

Points

20-34

-7

35-39

-3

40-44

0

45-49

3

50-54

6

55-59

8

60-64

10

65-69

12

70-74

14

75-79

16

Points

Total Cholesterol

Age 20-39

Age 40-49

Age 50-59

Age 60-69

Age 70-79

<160

0

0

0

0

0

160-199

4

3

2

1

1

200-239

8

6

4

2

1

240-279

11

8

5

3

2

≥280

13

10

7

4

2

Points

Age 20-39

Age 40-49

Age 50-59

Age 60-69

Age 70-79

Nonsmoker

0

0

0

0

0

Smoker

9

7

4

2

1

HDL (mg/dL)

Points

Systolic BP (mm Hg)

Points if Untreated

Points if Treated

≥60

-1

<120

0

0

50-59

0

120-129

1

3

40-49

1

130-139

2

4

<40

2

140-159

3

5

≥160

4

6

Point Total

10-yr Risk (%)

Point Total

10-yr Risk (%)

<9

<1

17

5

9

1

18

6

10

1

19

8

11

1

20

11

12

1

21

14

13

2

22

17

14

2

23

22

15

3

24

27

16

4

≥25

≥30

BP, blood pressure; HDL, high-density lipoprotein.

From Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;285:2486-2497, with permission.

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CORONARY ARTERY DISEASE

General Coronary Artery Disease and Stable Exertional Angina

GENERAL PRINCIPLES

Definition

Coronary artery disease (CAD) is most commonly defined as a >50% luminal stenosis of any epicardial coronary artery.

Chronic stable angina is the typical manifestation of ischemic heart disease in nearly half of patients with CAD.

Epidemiology

CAD is the leading cause of morbidity and mortality in Western Society.

Prevalence of CAD in the United States was 7.6% as of 2006 (American Heart Association, Heart Disease and Stroke Statistics 2009 Update).

Of the 16.8 million individuals in the United States carrying a diagnosis of CAD, 7.9 million presented as MI and 9.8 million as angina pectoris.

CAD was responsible for 35.3% of all U.S. deaths in 2005.

An estimated 785,000 Americans will have a first MI and 470,000 will have a recurrent MI in 2009. Another 195,000 will have a silent MI.

Etiology

CAD most commonly results from luminal obstruction by atheromatous plaque.

Other causes include congenital coronary abnormalities, myocardial bridging, vasculitis, prior radiation therapy, cocaine use, aortic stenosis, hypertrophic cardiomyopathy, coronary vasospasm, spontaneous coronary dissection, and syndrome X.

Pathophysiology

CAD manifestations include stable angina, ACS, CHF, sudden cardiac death, and silent ischemia.

ACS represents a continuum of clinical presentations ranging from UA to ST-segment elevation MI (STEMI). ACS most often results from acute thrombosis of a coronary artery at the site of atheromatous plaque rupture or ulceration.

Stable angina most often results from fixed coronary lesions that produce a mismatch between myocardial oxygen supply and demand. This mismatch is accentuated by increasing cardiac workload.

Anginal symptoms usually develop when a fixed stenosis reaches 70% or greater. In the setting of increased myocardial demand or diminished oxygen supply, the fixed stenosis does not permit adequate distal perfusion and ischemia results, manifesting itself as angina.

Risk Factors

Hypertension

Diabetes mellitus: The incidence of CAD in patients with diabetes is two to four times that of the general population. Insulin resistance, such as that seen with the metabolic syndrome, is associated with increased risk of CAD.

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Obesity increases the risk of CAD and is associated with additional cardiac risk factors, including hypertension, diabetes, and lipid abnormalities. A body mass index of >25 kg/m2 is considered overweight and >30 kg/m2 is obese.

Dyslipidemia: Elevated LDL, low HDL, and elevated triglycerides are independent risk factors for CAD.

Family history of premature CAD: Defined as first-degree male relative with CAD before age 55 or female relative before age 65.

Tobacco use is associated with a marked increase in risk of CAD. The risk is reversible and smoking cessation restores the risk of CAD to that of a nonsmoker within approximately 15 years (Arch Intern Med 1994 Jan 24;154(2):169-175).

Prevention

Aspirin (75 to 162 mg/d) should be considered in patients at higher risk of cardiovascular events (>10% risk of stroke or MI over 10 years). The U.S. Preventative Services Task Force recommends aspirin be used for men aged 45 to 79 and women aged 55 to 79 (http://www.ahrq.gov/clinic/USpstf/uspsasmi.htm#related).

Regular cardiovascular risk assessment commencing at age 20 and recurring every 5 years. The Framingham Risk Score is a commonly used algorithm for estimating risk of CAD (http://hp2010.nhlbihin.net/ATPiii/calculator.asp?usertype=prof).

Risk factor modification including tobacco cessation, treatment of hypertension, diabetes, obesity, and lipid control.

Initiation of statin therapy may limit the risk of developing CAD in addition to subsequent MI and cardiac mortality in select patients who have an elevated CRP (NEJM 2008;359:2195).

Current exercise guidelines recommend a minimum of 30 minutes of moderateintensity aerobic physical activity 5 days per week in addition to activities of daily living (Circulation 2007;116:1081-1093).

Hormone replacement therapy is not indicated for either primary or secondary CAD prevention in postmenopausal women.

Associated Conditions

Stable angina

Unstable angina

Non-ST-segment elevation MI (NSTEMI)

ST-segment elevation MI

Congestive heart failure

DIAGNOSIS

Clinical Presentation

History

Angina: Typical angina has three features: (i) substernal chest discomfort or heaviness with a characteristic quality and duration that is (ii) precipitated by stress and (iii) relieved by rest or nitroglycerin (NTG).

Atypical angina has two of these three features.

Noncardiac chest pain meets one or none of these characteristics.

The severity of angina may be quantified using the Canadian Cardiovascular Society (CCS) classification system (Table 16).

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Associated symptoms may include dyspnea, diaphoresis, nausea, vomiting, and dizziness.

Female patients and those with diabetes or chronic kidney disease may have minimal or atypical symptoms that serve as anginal equivalents. Such symptoms include dyspnea, epigastric pain, and nausea.

A careful history usually provides sufficient information to establish an appropriate pretest probability of CAD. For instance, in men and older women, the presence of typical angina in association with other cardiac risk factors is strongly predictive of CAD (Table 17).

Table 16 Canadian Cardiovascular Society Classification System

Class

Definition

CCS 1

Angina with strenuous activity

CCS 2

Angina with moderate activity (walking greater than two blocks or one flight of stairs)

CCS 3

Angina with mild activity (walking less than two blocks or one flight of stairs)

CCS 4

Angina that occurs with any activity or at rest

Anginal symptoms may include typical chest discomfort or anginal equivalents. CCS, Canadian Cardiovascular Society.

From Coronary Artery Dis 2004;15:111, with permission.

Physical Examination

Clinical exam should include measurement of BP, heart rate, and arterial pulses.

Cardiac exam findings including murmurs and gallops are of high importance.

Clinical stigmata of hyperlipidemia such as corneal arcus and xanthelasmas should be noted.

Signs of heart failure including an S3 gallop, rales on lung exam, elevated jugular venous pulsation, and peripheral edema may also be present.

Table 17 Pretest Probability of Coronary Disease (%)

Nonanginal Chest Pain

Atypical Angina

Typical Angina

Age (yr)

Men

Women

Men

Women

Men

Women

30-39

4

2

34

12

76

26

40-49

13

3

51

22

87

55

50-59

20

7

65

31

93

73

60-69

27

14

72

51

94

86

Pretest probability of CAD in Symptomatic Patients According to Age and Sex (Combined Diamond/Forrester and CASS Data). ACC/AHA 2002 Guideline Update for the Management of Patients with Chronic Stable Angina.

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Diagnostic Criteria

Angina is primarily a clinical diagnosis that is made based on history, clinical presentation and known risk of coronary artery disease. This diagnosis is often supported by diagnostic testing as outlined below.

First level list item 1

Second level list item 1

Differential Diagnosis

A wide range of disorders may manifest with chest discomfort and may include both cardiovascular and noncardiovascular etiologies (Table 18).

A careful history focused on cardiac risk factors, physical exam, and initial laboratory evaluation usually narrows the differential diagnosis.

Despite these efforts, further diagnostic testing is often required to determine the likelihood of CAD (see stress testing).

Table 18 Differential Diagnosis of Chest Pain

Diagnosis

Comments

Cardiovascular

Aortic stenosis

Anginal episodes can occur with severe aortic stenosis.

HCM

Subendocardial ischemia may occur with exercise and/or exertion.

Prinzmetal's angina

Coronary vasospasm that may be elicited by exertion or emotional stress.

Syndrome X

Ischemic chest pain in the presence of normal coronary arteries that is thought to be related to microvascular disease.

Pericarditis

Pleuritic chest pain associated with pericardial inflammation from infectious or autoimmune disease.

Aortic dissection

May mimic anginal pain and/or involve the coronary arteries.

Cocaine use

Results in coronary vasospasm and/or thrombus formation.

Other

Anemia

Marked anemia can result in a myocardial O2 supply-demand mismatch.

Thyrotoxicosis

Increase in myocardial demand may result in an O2 supply-demand mismatch.

Esophageal disease

GERD and esophageal spasm can mimic angina (responsive to NTG).

Biliary colic

Gallstones can usually be visualized on abdominal sonography.

Pneumonia

Usually visualized on chest x-ray. The pain may be pleuritic.

Musculoskeletal

Costochondritis (Tsetse's syndrome).

HCM, hypertrophic cardiomyopathy; GERD, gastroesophageal reflux disease; NTG, nitroglycerin.

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Diagnostic Testing

Stress testing and indications

Patients without known CAD:

Not indicated in asymptomatic patients as a screening test.

Patients with anginal symptoms.

Asymptomatic intermediate-risk patients who plan on beginning a vigorous exercise program or those with high-risk occupations (e.g., airline pilot).

Asymptomatic high-risk patients with risk factors such as diabetes or peripheral vascular disease.

Patients with known CAD:

Post-MI risk stratification (see section on STEMI).

Preoperative risk assessment.

Recurrent anginal symptoms despite medical therapy or revascularization.

Routine screening in asymptomatic patients after revascularization is controversial.

Exercise stress testing (ETT)

The test of choice for evaluating most patients of intermediate risk for CAD (Table 17).

Bruce Protocol: Consists of 3-minute stages of increasing treadmill speed and incline. BP, heart rate, and ECG are monitored throughout the study and the recovery period.

Specificity and sensitivity of 70% to 80% if the patient has a normal resting ECG and reaches the target heart rate (85% of maximal predicted heart rate for age).

The study is considered positive if:

New ST-segment depressions of >1 mm in multiple leads

Hypotensive response to exercise

Sustained ventricular arrhythmias are precipitated by exercise

The Duke Treadmill Score provides prognostic information for patients presenting with chronic angina (Table 19).

Stress testing with imaging

Recommended for patients with the following baseline ECG abnormalities:

Preexcitation (Wolf-Parkinson-White syndrome)

Left ventricular hypertrophy (LVH)

Left bundle branch block (LBBB) or paced rhythm

Intraventricular conduction delay (IVCD)

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Digoxin effects

Resting ST-segment or T-wave changes

Myocardial perfusion imaging. Commonly utilizes tracers Thalium-201 or technetium-99m in conjunction with exercise or pharmacologic stress. Perfusion imaging allows the diagnosis and localization of areas of ischemia and allows determination of ejection fraction. Myocardial viability can also be assessed via this technique. Nuclear perfusion stress imaging has a sensitivity of 85% to 90% and specificity of 70%.

Echocardiographic imaging. Exercise or dobutamine stress testing can be performed with echocardiography to aid in the diagnosis of CAD. As with nuclear imaging, echocardiography adds to the sensitivity and specificity of the test by revealing areas with wall motion abnormalities. The technical quality of this study can be limited by imaging quality (i.e., obesity). Stress echocardiography has a sensitivity of 75% and specificity of 85% to 90%.

Magnetic resonance perfusion imaging with adenosine utilizing contrast enhancement is another tool to evaluate myocardial ischemia and viability.

Pharmacologic stress testing

In patients who are unable to exercise, pharmacologic stress testing may be preferable.

Dipyridamole, adenosine, and regadenoson are vasodilators that are commonly used in conjunction with myocardial perfusion scintigraphy. These agents are the agents of choice in patients with LBBB or paced rhythm on ECG due to the increased incidence of false-positive stress tests with either exercise or dobutamine infusion.

Dobutamine is a positive inotrope commonly used with echocardiographic stress tests.

Contraindications to stress testing

Acute MI within 2 days

UA not previously stabilized by medical therapy

Cardiac arrhythmias causing symptoms or hemodynamic compromise

Symptomatic severe aortic stenosis

Symptomatic heart failure

Acute pulmonary embolus, myocarditis, pericarditis, or aortic dissection

Table 19 Exercise Stress Testing: Duke Treadmill Score Score

Minutes exercised - [5 × maximum ST-segment deviation] - [4 × anginal score]

Score

Angina score: 0 = none, 1 = not test limiting, 2 = test limiting

>5

Annual mortality 0.25%

Medical therapy

-10 to 4

Annual mortality 1.25%

Further testing based on risk factors and imaging

<-10

Annual mortality >5%

Coronary angiography

In general β-blockers, other nodal blocking agents, and nitrates should be discontinued prior to stress testing.

From NEJM 1991;325:849, with permission.

Diagnostic Procedures

Coronary Angiography

The gold standard for evaluating coronary anatomy that quantifies the presence and severity of atherosclerotic lesions.

Should be performed in patients with known or suspected angina with a markedly positive stress test or who have survived sudden cardiac death.

Can be used to evaluate patients who are suspected of having a nonatherosclerotic cause of ischemia (e.g., coronary anomaly, coronary dissection, radiation vasculopathy).

Consider cardiac catheterization in patients who have recurrent chest pain despite aggressive medical therapy for angina.

Can assist in the diagnosis of vasospasm.

Intravascular ultrasound (IVUS): Can assess plaque burden, providing definitive assessment of the coronary vasculature at time of catheterization.

Coronary flow reserve as measured by Doppler or pressure techniques aids in the assessment of the functional significance of a stenotic lesion.

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Left ventricular catheterization: Allows measurement of LV filling pressure, aortic valve gradient, and an assessment of regional wall motion via contrast ventriculography.

Noninvasive alternatives to coronary angiography include coronary CT angiography and magnetic resonance angiography. These modalities are currently under intensive study. Compared to invasive coronary angiography, CT angiography has a sensitivity of 80% to 90% and specificity of 85% (Circulation 2006;114:2334). This modality is limited by radiation exposure, requirement for HR less than 70 bpm, and presence of coronary calcification or stents.

TREATMENT

The major goal of treatment in patients with stable angina is to prevent MI, cardiac death, and to reduce symptoms.

A combination of lifestyle modification, medical therapy, and coronary revascularization should be employed. A recommended strategy for the evaluation and management of the patient with stable angina can be found in Figure 1.

Medical treatment is aimed at improving myocardial oxygen supply, reducing myocardial oxygen demand, controlling exacerbating factors (anemia, valvular disease), and limiting the development of further atherosclerotic disease.

Aspirin (75 to 162 mg/d) reduces cardiovascular events including repeat revascularization, MI, and cardiac death by approximately 33% (BMJ 1994;308:81; Lancet 1992;114:1421).

Aspirin desensitization may be performed in selected patients with aspirin allergy.

Clopidogrel (75 mg/d) can be used in patients who are allergic or intolerant of aspirin.

Dual therapy with aspirin and clopidogrel may reduce the incidence of adverse cardiac outcomes in high-risk patients such as those with a prior MI (NEJM 2006;354:1706; JACC 2007;49:1982).

β-Adrenergic antagonists (Table 20) control anginal symptoms by decreasing heart rate and myocardial work leading to reduced myocardial oxygen demand.

The dosage can be adjusted to result in a resting heart rate of 50 to 60 bpm.

Use of β-blockers is contraindicated in patients with severe active bronchospasm, significant AV block, marked resting bradycardia, or poorly compensated HF.

β-Blockers may worsen coronary vasospasm and should be avoided in such patients.

Calcium channel blockers can be used either in conjunction with or in lieu of β-blockers in the presence of contraindications or adverse effects (Table 21).

Calcium antagonists are often used in conjunction with β-blockers if the latter are not fully effective at relieving anginal symptoms. Both long-acting dihydropyridines and nondihydropyridine agents can be used.

Calcium channel blockers are effective agents for the treatment of coronary vasospasm.

The use of short-acting dihydropyridines (nifedipine) should be avoided due to the potential to increase the risk of adverse cardiac events (Circulation 1995;92: 1326).

Nitrates, either long-acting formulations for chronic use or sublingual preparations for acute anginal symptoms, can be used as adjunctive antianginal agents (Table 22).

Sublingual preparations should be used at the first indication of angina or prophylactically before engaging in activities that are known to precipitate angina.

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Patients should seek prompt medical attention if angina occurs at rest or fails to respond to the third sublingual dose.

Nitrate tolerance resulting in reduced therapeutic response may occur with all nitrate preparations. The institution of a nitrate-free period of 10 to 12 hours (usually at night) can enhance treatment efficacy.

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ACE inhibitors may have additive benefit in the treatment of stable angina.

A reduction of exercise-induced myocardial ischemia has been reported with the addition of an ACE inhibitor in patients with stable angina and normal LV function receiving optimal β-blocker therapy (NEJM 2004;351:2048; Lancet 2003;362:782).

ACEI therapy in high-risk patients with vascular disease or diabetes and at least one other cardiovascular risk factor reduced the rate of death, MI, or stroke (NEJM 2000;342:145).

Ranolazine is a novel antianginal agent that does not depend upon reductions in heart rate or BP. Its exact mechanism of action is unknown; however, it appears to have effect on cardiomyocyte metabolism and sodium ion channel function.

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It has shown benefit in the symptomatic relief of refractory angina (Clin Ther 2006;28:1996).

Cholesterol-lowering agents including statins, fibrates, bile acid sequestrants, and niacin reduce recurrent events and improve overall outcome in patients with established CAD.

HMG-CoA reductase inhibitors (statins) are the best studied agents and have been shown to limit atherosclerotic burden and reduce cardiac outcomes in patients with CAD (Lancet 2002;360:7; 4S: Lancet 1994;344:1383; NEJM 1996; 355:1001).

Recent studies have demonstrated that more intensive statin therapy is superior in preventing cardiovascular outcomes (NEJM 2005;352:1425; NEJM 2004; 350:1495).

Coronary revascularization

In general, medical therapy with at least two, and preferably three, classes of antianginal agents should be attempted before this approach is considered a failure and coronary revascularization pursued.

In patients with stable angina and preserved LV function, medical therapy results in similar cardiovascular outcomes when compared to percutaneous coronary intervention (PCI). Of the patients who receive medical therapy only, there is a higher need for revascularization to control anginal symptoms (NEJM 2007;256:1503; RITA-2: Lancet 1997;350:461).

PCI and/or coronary artery bypass graft (CABG) surgery is indicated in patients who present with the following:

Angina refractory to medical therapy

Angina and reduced LV function

Severe activity limiting angina (CCS class III-IV)

Angina in the presence of left main or severe three-vessel CAD

The choice between PCI and CABG is dependent on the coronary anatomy, medical comorbidities, and patient preference. CABG is preferred in diabetics with multivessel disease and LV dysfunction (BARI: NEJM 1996;335:217).

The Syntax trial compared PCI versus CABG in patients with previously untreated three-vessel CAD or left main CAD. The study demonstrated an

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increased risk of major adverse cardiac and vascular events in the PCI group attributable to repeat intervention (Syntax: N Engl J Med 2009 March 5;360: 961).

CABG carries a 1% to 3% mortality rate, 5% to 10% incidence of perioperative MI, and a small risk of perioperative stroke. The use of internal mammary artery grafts is associated with 90% graft patency at 10 years, compared with 40% to 50% for saphenous vein grafts. The long-term patency of a radial artery graft is 80% at 5 years. After 10 years of follow-up, 50% of patients develop recurrent angina or other adverse cardiac events related to late vein graft failure or progression of native CAD (NEJM 1996;334:216).

The risks of elective PCI include <1% mortality, a 2% to 5% rate of nonfatal MI, and <1% need for emergent CABG for an unsuccessful procedure. Patients undergoing PCI have shorter hospital stays and similar outcomes with respect to subsequent cardiac events and mortality compared to those undergoing CABG. PCI does have a higher rate of target lesion stenosis that can be minimized using drug-eluting stents (DES) (NEJM 2005;352:2174).

Alternative therapies are available for patients with chronic stable angina who are refractory to medical management and who are not candidates for further percutaneous or surgical revascularization.

Transmyocardial laser revascularization has been delivered by percutaneous and epicardial surgical techniques. Surgical transmyocardial laser revascularization has been shown to improve symptoms in patients with stable angina, although the mechanism that is responsible is controversial. No benefit has been demonstrated in terms of increasing myocardial perfusion or mortality.

Therapeutic angiogenesis is a novel approach that aims to facilitate the growth of collateral blood vessels by delivering proangiogenic growth factors (VEGF and FGF) to the myocardium. Small studies have suggested some benefit in exercise capacity and myocardial perfusion.

Figure 1. Approach to the evaluation and management of the patient of stable angina. Patients with clinical heart failure, severe limiting angina, and those with LV dysfunction should undergo coronary angiography to define underlying coronary artery disease. Patients without the above features may undergo further risk stratification with stress testing. Following stress testing, patients may undergo either coronary angiography or empiric medical therapy depending on their risk profile. Patients initially treated with medical therapy who have refractory systems should undergo angiography. 1PCI results in equivalent cardiovascular outcomes to CABG with the exception of increased target vessel revascularization. 2PCI should be reserved for patients who have high-grade lesions, severe ischemia, and those refractory to medical therapy. NYHA, New York Heart Association; CCS, Canadian Cardiovascular Society Classification (angina); LV, left ventricle; WMA, wall motion abnormality; CABG, coronary artery bypass grafting; PCI, percutaneous coronary intervention; NICM, nonischemic cardiomyopathy.

Table 20 β-Blockers Commonly Used for Ischemic Heart Disease

Drug

β-Receptor Selectivity

Dose

Propranolol

β1 and β2

20-80 mg bid

Metoprolol

β1

50-200 mg bid

Atenolol

β1

50-200 mg daily

Nebivolol

β1

5-40 mg daily

Nadolol

β1 and β2

40-80 mg daily

Timolol

β1 and β2

10-30 mg tid

Acebutolol

β1

200-600 mg bid

Bisoprolol

β1

10-20 mg daily

Esmolol (IV)

β1

50-300 mcg/kg/min

Labetalol Combined

α, β1, β2

200-600 mg bid

Pindolol

β1 and β2

2.5-7.5 mg tid

Carvedilol

Combined α, β1, β2

3.125-25 mg bid

Table 21 Calcium Channel Blockers Commonly Used for Ischemic Heart Disease

Drug

Duration of Action

Usual Dosage

Dihydropyridines

Nifedipine

Slow release

Long

30-180 mg/d

Amlodipine

Long

5-10 mg/d

Felodipine (SR)

Long

5-10 mg/d

Isradipine (SR)

Medium

2.5-10 mg/d

Nicardipine

Short

20-40 mg tid

Nondihydropyridines

Diltiazem

Immediate release

Short

30-80 mg qid

Slow release

Long

120-360 mg/d

Verapamil

Immediate release

Short

80-160 mg tid

Slow release

Long

120-480 mg/d

Table 22 Nitrate Preparations Commonly Used for Ischemic Heart Disease

Preparation

Dosage

Onset (min)

Duration

Sublingual nitroglycerin

0.3-0.6 mg prn

2-5

10-30 min

Aerosol nitroglycerin

0.4 mg prn

2-5

10-30 min

Oral isosorbide dinitrate

5-40 mg tid

30-60

4-6 hr

Oral isosorbide mononitrate

10-20 mg bid

30-60

6-8 hr

Oral isosorbide mononitrate SR

30-120 mg daily

30-60

12-18 hr

2% Nitroglycerin ointment

0.5-2.0 in. tid

20-60

3-8 hr

Transdermal nitroglycerin patches

5-15 mg daily

>60

12 hr

Intravenous nitroglycerin

10-200 mcg/min

<2

During infusion

PATIENT EDUCATION

Compliance with medications, diet, and exercise should be stressed to patients. All patients should be encouraged to participate in cardiac rehab as well as meet with a registered dietician.

Patients with known CAD should present for evaluation if any change in chest pain pattern, frequency, or intensity develops.

Patients should also be evaluated if they report the presence of any HF symptoms including dyspnea, orthopnea, or paroxysmal nocturnal dyspnea.

MONITORING/FOLLOW-UP

Close patient follow-up is a critical component of the treatment of CAD as lifestyle modification and secondary risk factor reduction require serial reassessment and interventions.

Relatively minor changes in anginal symptoms can be safely treated with titration and/or addition of antianginal medications.

Significant changes in anginal complaints (frequency, severity, or time to onset with activity) should be evaluated by either stress testing (usually in conjunction with an imaging modality) or cardiac catheterization as warranted.

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Patients with angina refractory to medical therapy should be considered for coronary revascularization if the anatomy is amenable to revascularization.

Acute Coronary Syndrome—Unstable Angina and Non-ST-segment Elevation MI

GENERAL PRINCIPLES

Definition

Acute coronary syndrome (ACS) refers to any constellation of clinical symptoms that are compatible with acute myocardial ischemia. For simplicity, ACS can be divided into STEMI, NSTEMI, and UA.

STEMI results from complete and prolonged occlusion of an epicardial coronary blood vessel and is defined based on ECG criteria (ST-segment elevation greater than 0.1 mV in at least two contiguous leads or a new LBBB).

NSTEMI and UA are considered to be closely related conditions whose pathogenesis and clinical presentations are similar but differ in severity. NSTEMI usually results from severe coronary artery narrowing, transient occlusion, or microembolization of thrombus and/or atheromatous material. If the stenosis is not severe enough or the occlusion does not persist long enough to cause myocardial necrosis (as indicated by positive biomarkers), the syndrome is labeled UA.

Approximately three-fourths of patients presenting with UA/NSTEMI will have an abnormal ECG, more often seen as labile ST-segment depression or T-wave inversions, or less frequently transient ST-segment elevations.

The diagnosis of UA confers a 10% to 20% risk of progression to acute MI in the untreated patient. Medical treatment reduces this risk to 5% to 7%.

NSTEMI is defined by an elevation of cardiac enzymes (creatine kinase MB [CK-MB] or troponin) and the absence of persistent ST-segment elevation. In the absence of elevated cardiac enzymes, the syndrome is termed UA.

The management of ACS should focus on rapid diagnosis, risk stratification, and institution of therapies that restore coronary blood flow and reduce myocardial ischemia.

Epidemiology

ACS accounts for almost 1.6 million hospitalizations each year (Circulation 2006;113:e85; JACC 2007;50:e1).

Among patients with ACS, approximately 60% have UA and 40% have MI, either NSTEMI or STEMI.

Of the patients with MI, two-thirds present with an NSTEMI and the remaining one-third present with an acute STEMI.

At 1 year, patients with UA/NSTEMI are at considerable risk for death (~6%), recurrent MI (~11%), and need for revascularization (~50% to 60%). It is important to note that although the short-term mortality of STEMI is greater than that of NSTEMI, the long-term mortality is the same (JACC 2007;50:e1; JAMA 1996;275: 1104).

Pathophysiology

Myocardial ischemia results from decreased myocardial oxygen supply and/or increased demand. In the majority of cases, NSTEMI is due to a sudden decrease

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in blood supply via partial occlusion of the affected vessel. In some cases, marked increased myocardial oxygen demand may lead to NSTEMI, as seen in severe anemia or hypertensive crisis.

UA/NSTEMI most often represents acute atherosclerotic plaque rupture and superimposed thrombus formation. Alternatively, it may also be due to progressive mechanical obstruction from advancing atherosclerotic disease, in-stent restenosis (ISR), or bypass graft disease.

Atherosclerotic plaques that are prone to rupture are termed vulnerable plaques. Vulnerable plaques often do not cause critical stenosis and thus may be difficult to identify by angiography alone. Experimental imaging modalities that may identify vulnerable plaques prior to rupture are currently being evaluated.

Plaque rupture may be triggered by local and/or systemic inflammation as well as shear stress. Rupture leads to exposure of lipid-rich subendothelial components to circulating platelets and inflammatory cells serving as a potent substrate for thrombus formation.

Less common causes include dynamic obstruction of the coronary artery due to vasospasm (Prinzmetal angina), syndrome X, coronary vasculitis, dissection, embolus, and myocardial bridge.

Risk Factors

The approach to clinical testing, pharmacologic treatment, and timing of possible invasive therapy is guided by the probability of progression to MI and/or reinfarction and risk of subsequent mortality.

Patients at highest risk for progression to MI include those with:

Rest angina

Associated dynamic ischemic ECG changes (ST-segment deviations or T-wave inversions)

Continued symptoms despite initiation of medical therapy

Several clinical tools have been developed to estimate a patient's risk of MI and cardiac mortality, including the TIMI (Thrombolysis in Myocardial Infarction) and GRACE (Global Registry of Acute Coronary Events) risk score.

The TIMI risk score can be used to determine the patient's short-term risk of death or nonfatal MI (JAMA 2000;284:835). Patients can be classified as low, intermediate, or high risk on the basis of their clinical profile (Fig. 2).

Low-risk patients (TIMI 0 or 1) may be observed with cardiac monitoring in a chest pain or observation unit.

If the patient remains chest pain free, has normal cardiac enzymes, and has no clinical signs of HF, a noninvasive stress test should be obtained for further risk stratification.

Patients should have negative cardiac enzymes for 24 hours prior to stress testing. If a patient presents with positive cardiac enzymes and noninvasive testing is selected, a submaximal or pharmacologic stress test 72 hours after the peak value may be performed.

Low-risk patients with a positive stress test should be managed with medication and invasive testing individualized based on clinical status and the severity of the ischemic burden.

Intermediate- and high-risk patients should be admitted to the hospital for observation and management.

Patients with ongoing symptoms should be admitted to the ICU for more aggressive monitoring with consideration for urgent cardiac catheterization.

Intermediate- and high-risk patients should undergo noninvasive stress testing or coronary angiography based on their clinical course and risk profile (see below).

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Figure 2. Top. 14-day rates of death, MI, or urgent revascularization from the TIMI 11B and ESSENCE trials based on increasing TIMI risk score. Coronary artery disease (CAD) risk factors include family history of CAD, diabetes, hypertension, hyperlipidemia, and tobacco use. TIMI, Thrombolysis in Myocardial Infarction; MI, myocardial infarction. (Adapted from JAMA 2000;284:835-842.) Bottom. Differing management strategies in patients with ACS based on TIMI risk score. UFH, unfractionated heparin; LWMH, low-molecular-weight heparin; ASA, aspirin; dual antiplatelet therapy includes either ASA and clopidogrel or ASA and a glycoprotein IIb/IIIa inhibitor; triple antiplatelet therapy denotes ASA, clopidogrel, and a glycoprotein IIb/IIIa inhibitor.

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DIAGNOSIS

Initial assessment of the patient with UA/NSTEMI includes the clinical presentation (history and physical examination), 12-lead ECG, and measurement of cardiac-specific biomarkers (troponin or CK-MB).

Clinical Presentation

History

The three principal presentations for UA are rest angina (angina occurring at rest and prolonged, usually >20 minutes), new-onset angina, and progressive angina (previously diagnosed angina that has become more frequent, lasts longer, or occurs with less exertion). New-onset and progressive angina should occur with at least mild to moderate activity (CCS class III severity).

Physical Examination

Evaluation and management should be individualized based on the patient's clinical presentation, risk factors, and ECG. A physical exam should be performed focusing on objective evidence of HF, including peripheral hypoperfusion, heart murmur, elevated jugular venous pulsation, pulmonary edema, and peripheral edema.

The presence of severe underlying coronary disease is suggested in patients with refractory chest discomfort, clinical evidence of LV dysfunction such as CHF, hypotension, and new ECG changes that are consistent with myocardial ischemia.

Laboratories

Biochemical makers

A CBC, fasting glucose, and lipid profile should be obtained in all patients with suspected CAD.

High-sensitivity CRP, lipoprotein A, and homocysteine are all associated with increased risk of CAD; however, these markers have not yet been embraced in standard of care guidelines.

Diagnostic Testing

Electrocardiography

A baseline ECG should be recorded in all patients with suspected CAD. A normal tracing does not exclude the presence of disease.

Possible indicators of CAD include significant Q waves, ST-segment changes, and T-wave inversions.

If the patient is experiencing anginal symptoms, serial ECGs should be obtained to assess for dynamic ischemic changes.

Imaging

Chest x-ray can be helpful by providing information on heart size and lung parenchyma.

Should be obtained in patients with evidence of CHF, valvular heart disease, or aortic disease.

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Echocardiogram permits measurement of global LV systolic, wall motion abnormalities, diastolic function, and valvular disease. LV function may guide appropriate medical or surgical therapy, rehabilitation, and work status.

May be helpful in establishing pathophysiologic mechanisms and guiding therapy in patients with heart failure in addition to angina.

Additional imaging modalities including coronary calcium screening (CAC) and carotid intima-media thickness may play an important role in the at-risk patient, but have limited role in the symptomatic patient.

Laboratories

Measurement of cardiac-specific markers

Cardiac biomarkers are essential in the diagnosis of UA/NSTEMI and should be obtained in all patients who present with chest discomfort suggestive of ACS. In patients with negative cardiac markers within 6 hours of the onset of pain, a second sample should be drawn within 6 to 12 hours. The most commonly measured markers are troponins, CK-MB, and myoglobin (Table 23).

Cardiac-specific troponin is the preferred marker and should be measured in all patients.

Troponin T and I assays are highly specific and sensitive markers of myocardial necrosis. Serum troponin levels are usually undetectable in normal individuals, and any elevation is considered abnormal.

MI size and risk of subsequent cardiac death is directly proportional to the absolute increase in cardiac-specific troponin (NEJM 1996;335:1333; Circulation 1998;98:1853).

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CK-MB is also an acceptable marker of myocardial necrosis, but lacks specificity, as it is present in both skeletal and cardiac muscle cells.

Specificity can be improved by using the CK-MB/total CK fraction. A CK-MB fraction greater than 2.5% is suggestive of myocardial injury.

CK-MB is a useful assay for detecting postinfarct ischemia, as a fall and subsequent rise in enzyme levels suggests reinfarction.

Similarly, CK-MB levels are often followed after percutaneous revascularization. Small rises in CK-MB often represent distal microembolization, while large rises suggest more significant complications, such as acute stent thrombosis.

Myoglobin is released more rapidly following myocardial damage than either CK-MB, troponin T, or troponin I, but lacks specificity.

Lactate dehydrogenase (LDH), alanine transaminase (ALT), and aspartame transaminase (AST) are nonspecific markers of myocardial necrosis and should not be used.

C-reactive protein levels may aid in initial risk assessment in ACS patients and predict mortality independent of troponin elevations (JACC 1998;31:1460).

Table 23 Cardiac Biomarkers

Detectable

Peak

Return to Baseline

Troponin I, T

3-6 hr

24-36 hr

5-14 d

CK-MB

2-6 hr

12-18 hr

24-48 hr

Myoglobin

1-2 hr

6-8 hr

12-24 hr

Electrocardiography

A 12-lead ECG should be obtained immediately in patients with ongoing chest discomfort and as rapidly as possible in patients whose chest discomfort subsided prior to evaluation.

Approximately 50% of patients with UA/NSTEMI have significant ECG abnormalities, including transient ST-segment elevations, ST depressions, and T-wave inversions (JACC 2007;50:e1).

ST-segment depression >0.05 mV (0.5 mm) in two contiguous leads is a sensitive indicator of myocardial ischemia, especially if dynamic and associated with symptoms.

Symmetrical T-wave inversions of >0.2 mV (2 mm) across the precordium (Wellens' waves) are strongly suggestive for myocardial ischemia and particularly worrisome for a critical lesion in the left anterior descending (LAD) artery distribution.

Nonspecific ST-segment changes or T-wave inversions (those that do not meet voltage criteria) are less helpful.

TREATMENT

Goals of therapy. In addition to prompt risk stratification, patients presenting with UA/NSTEMI should receive medications that reduce myocardial ischemia through reduction in myocardial oxygen demand, improvement in coronary perfusion, and prevention of further thrombus formation.

Early conservative versus invasive strategies. Two different strategies have evolved for patients with UA/NSTEMI (Fig. 3).

Early conservative strategy. The patient is treated with medical therapy at maximally tolerated doses and coronary angiography is reserved for patients with evidence of recurrent ischemia despite medical therapy or a positive stress test. Although the choice should always be individualized to a particular patient, in general, an early conservative approach can be used in low-risk patients and selected intermediate-risk patients without adverse effects on clinical outcomes.

Early invasive strategy. Patients are routinely referred for coronary angiography and subsequent revascularization, as warranted. High-risk patients, including those with recurrent ischemia on medical therapy, evidence of myocardial injury, CHF, LV dysfunction, sustained ventricular tachycardia (VT), or prior coronary revascularization (PCI within 6 months or CABG), are best assessed with an early invasive approach. Angiography in these individuals defines coronary anatomy and directs the choice of revascularization options, if appropriate.

An early invasive strategy is also warranted in low- or intermediate-risk patients with repeated ACS presentations despite appropriate therapy. Cardiac catheterization provides the means to distinguish between those with no significant coronary disease and those with anatomy that is amenable to revascularization.

Multiple clinical trials and meta-analysis have demonstrated the benefit of an early invasive strategy in high-risk (and possibly intermediate risk) patients, especially those with refractory angina, new or dynamic ST-segment changes, elevated cardiac enzymes, diabetes, and high TIMI risk scores (Lancet 1999;354:708; NEJM 2001;344:1879; JAMA 2003;290:1593; Lancet 2002;360:743; NEJM 2009;360:2165; JAMA 2005;293:2908).

Patients with mild to moderate renal insufficiency (creatinine clearance greater than 30) also benefit from an early invasive strategy. No benefit was seen in patients with a creatinine clearance less than 30 or those receiving dialysis (Circulation 2009;120:851).

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Figure 3. Diagnostic and therapeutic approach to patients presenting with ACS focusing on antiplatelet and antithrombotic therapy. *Bivalirudin and fondaparinux are appropriate alternatives to UFH and LMWH. †Clopidogrel should be given when there is a reasonable certainty that the patient will not require CABG. GP IIb/IIIa inhibitors can be used as an alternative to clopidogrel when dual antiplatelet therapy is indicated and need for CABG is possible. In this setting, clopidogrel can be given after diagnostic angiography. ††GP IIb/IIIa inhibitors can be administered, in addition to ASA and clopidogrel, in high-risk patients. #Indicators of recurrent ischemia include worsening chest pain, increasing cardiac enzymes, and dynamic ECG changes. 1GP IIb/IIIa inhibitors should be continued per cath lab protocols. 2UFH, LWMH, or alternative agents should be continued for 48 to 72 hours. 3Clopidogrel should be given to patients with likely CAD who elected for a conservative approach and to patients who presented with myocardial injury. ACS, acute coronary syndrome; STEMI, ST-segment elevation myocardial infarction; NSTEMI: non-ST-segment elevation myocardial infarction; Rx, treatment; UFH, unfractionated heparin; LMWH, low-molecular-weight heparin; GP IIb/IIIa, glycoprotein IIb/IIIa inhibitor; EF, ejection fraction; CAD, coronary artery disease; CABG, coronary artery bypass grafting; PCI, percutaneous coronary intervention; WMA, wall motion abnormality. (Adapted from the ACC/AHA 2007 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction.)

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Medications

The goal of pharmacologic treatment is to provide relief from chest pain and limit thrombus formation through inhibition of platelet activation and aggregation.

This approach should include antiplatelet, anticoagulant, and antianginal medications (Table 24).

All patients presenting with UA/NSTEMI should be restricted to bedrest and provided supplemental oxygen as needed.

Antiplatelet therapy (Table 25)

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All patients should receive aspirin (ASA) unless a contraindication exists.

ASA effectively blocks platelet aggregation within minutes and should be administered immediately by EMS or on arrival to the ER.

The only contraindications to ASA therapy are a history of documented drug allergy and active bleeding. Patients with an ASA allergy should immediately receive clopidogrel (see below), and an allergy consultation should be obtained for possible desensitization.

Clopidogrel (Plavix), Ticlopidine (Ticlid), and Prasugrel (Effient) are ADP receptor antagonists that inhibit platelet activation and aggregation. Clopidogrel is preferred over ticlopidine because of a lower risk of gastrointestinal bleeding, neutropenia, and thrombotic thrombocytopenic purpura (TTP). Prasugrel was recently approved by the FDA for treatment of patients following ACS.

Clopidogrel can be used in patients who are intolerant or allergic to aspirin.

A minimum of 1 month of therapy should be given if medical or percutaneous treatment is planned and ideally continued for at least 1 year. The length of treatment will depend upon the type of stent placed (see section on STEMI).

The issue of CABG surgery is of particular concern with regards to clopidogrel administration and timing. It is currently recommended that clopidogrel be withheld from patients for at least 5 days prior to CABG, given the risk of bleeding and its long drug half-life.

- A recent multicentered study demonstrated that the increased risk of bleeding from clopidogrel therapy may be restricted to the first 2 to 3 days following drug cessation (JACC 2008;52(21):1693).

- Intermediate- to high-risk patients should receive dual antiplatelet therapy upon presentation regardless of their likelihood of requiring CABG. Glycoprotein IIb/IIIa antagonists (see below) are potent IV agents with a short plasma half-life and are thus attractive alternatives to clopidogrel in this setting.

Clopidogrel resistance is a newly recognized entity that confers increased risk of adverse outcomes in patients presenting with ACS. A polymorphism in the CYP2C19 gene has been associated with decreased platelet inhibition and increased risk of major adverse cardiovascular outcomes in patients receiving clopidogrel (NEJM 2009;360:354; NEJM 2009;360:363).

- Reduced CYP2C19 activity leads to impaired cytochrome P450-mediated conversion of clopidogrel to its active metabolite.

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- Clopidogrel resistance can be screened for using point-of-care platelet inhibition assays or genotyping.

- Proposed strategies to combat clopidogrel resistance include elevated clopidogrel dosing and first-line use of prasugrel, which does not require cytochrome P450-mediated conversion to an active metabolite.

Prasugrel has increased potency and results in greater and more uniform platelet inhibition compared to clopidogrel. While it decreased adverse outcomes in patients following ACS, prasugrel treatment increased bleeding rates and should be avoided in patients older than 75 years, less than 60 kg, and those with prior stroke or TIA.

Glycoprotein IIb/IIIa (GP IIb/IIIa) antagonists block the interaction between platelets (GP IIb/IIIa receptor) and fibrinogen, thus targeting the final common pathway for platelet aggregation. GP IIb/IIIa inhibitors (abciximab, eptifibatide, or tirofiban) should be considered in the treatment of all high-risk patients with refractory UA/NSTEMI, especially those with significant ST-T changes or elevated cardiac enzymes.

- GP IIb/IIIa antagonists should be used in conjunction with therapeutically dosed unfractionated heparin (UFH) or enoxaparin.

- The utility of GP IIb/IIIa antagonists in conjunction with ASA, clopidogrel, and heparin therapy appears to be restricted to patients with elevated

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cardiac biomarkers and those with diabetes (JAMA 2006;295:1531; Circulation 2001;104:2767; NEJM 2009;360:2176).

- GP IIb/IIIa antagonists may be used as an alternative to clopidogrel in intermediate- to high-risk patients presenting with UA/NSTEMI that may require surgical revascularization.

- GP IIb/IIIa antagonists increase the risk of major bleeding, especially when used in combination with clopidogrel.

- Thrombocytopenia, which can be severe, is an uncommon complication of all these agents and should prompt discontinuation of the drug.

Anticoagulant therapy (Table 26)

Anticoagulation is a key component in the management of patients with ACS and should be routinely used in conjunction with ASA. Available therapeutic agents include intravenous UFH, enoxaparin (low-molecular-weight heparin [LMWH], fondaparinux, and bivalirudin (Angiomax).

UFH and LMWH minimize thrombus formation by inhibiting factors IIa and Xa, respectively. The use of both agents is limited by heparin-induced thrombocytopenia (HIT).

Fondaparinux is a synthetic polysaccharide that contains the same pentasaccharide sequence found in UFH and LMWH. It selectively inhibits factor Xa and does not bind PF4, making HIT unlikely with its use.

Bivalirudin (Angiomax) is a direct thrombin inhibitor. Bivalirudin can be given in conjunction with ASA and clopidogrel in patients presenting with UA/NSTEMI who will undergo an early invasive strategy.

Bivalirudin is particularly useful in the management of both cardiac and cardiac surgery patients with HIT.

Thrombolytic therapy is not indicated in UA/NSTEMI and has been shown to increase mortality.

Anti-ischemic therapy (Table 27)

Nitroglycerin reduces myocardial oxygen demand and enhances myocardial oxygen delivery. The choice of preparation depends on the severity of symptoms.

Treatment can be initiated at the time of presentation with sublingual nitroglycerin.

Less stable patients or those who require additional agents to control significant hypertension should be treated with intravenous nitroglycerin until pain relief, hypertension control, or both are achieved.

β-Adrenergic blockers limit cardiac ischemia by reducing myocardial oxygen demand and should be started early in the absence of contraindications. In high-risk patients, intravenous, followed by oral, preparations can be used. Treatment with an oral preparation alone is acceptable, especially if the patient is intermediate to low risk or is unable to tolerate intravenous agents.

The goals of therapy are to reduce the heart rate to 60 bpm and maintain an SBP greater than 90 to 100 mm Hg.

Contraindications to β-blocker therapy include advanced AV block, active bronchospasm, decompensated CHF, cardiogenic shock, hypotension, and bradycardia.

Calcium channel blockers can be used as third-line agent in patients continuing to have chest pain in the setting of adequate β-blocker and nitrate therapy.

Nifedipine, amlodipine, diltiazem, and verapamil appear to have similar coronary dilatory properties. Neither of these agents has demonstrated an effect on mortality or recurrent MI.

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Calcium channel blockers are useful in vasospastic angina, cocaine-induced vasospasm, and among patients in whom β-blockade is contraindicated.

Ranolazine is a novel antianginal agent that is useful in the treatment of chronic stable angina. Addition of ranolazine to standard medical therapy does not reduce recurrent ischemia, MI, or death in patients presenting with UA/NSTEMI (JAMA 2007;297:1775).

Blood transfusion improves oxygen-carrying capacity and myocardial oxygen supply. The potential benefit of routine blood transfusions in patients presenting with an NSTEMI is based on limited clinic data (NEJM 2001;345:1230).

The recommended target hemoglobin and hematocrit is 10 mg/dL and 30%, respectively.

Patients presenting with UA/NSTEMI who are actively bleeding and/or significantly anemic should be transfused routinely.

Other medical therapies

ACE inhibitors are effective antihypertensive agents and have been shown to reduce mortality in patients with CAD and LV systolic dysfunction.

ACE inhibitors should be used in patients with LV dysfunction (EF <40%), hypertension, or diabetes presenting with ACS. ARBs are appropriate in patients who cannot tolerate ACE inhibitors (NEJM 2003;349:1893).

HMG-CoA reductase inhibitors (statins) are potent lipid-lowering agents that reduce the incidence of ischemia, MI, and death in patients with CAD. Statins should be routinely administered within 24 hours of presentation in patients presenting with ACS.

Statin therapy reduces adverse outcomes through lipid lowering, anti-inflammatory, and atherosclerotic plaque-stabilizing effects.

Aggressive statin therapy reduces the risk of recurrent ischemia, MI, and death in patients presenting with ACS (JAMA 2001;285:1711).

The reduction in adverse outcomes following early initiation of aggressive lipid lowering to target LDL less than 70 therapy can be seen within 30 days following initial presentation (NEJM 2004;350:1495). Aggressive LDL lowering also reduces the incidence of peri-procedural MI following PCI (JACC 2007;49: 1272).

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NSAIDS are associated with an increased risk of death, MI, myocardial rupture, hypertension, and HF in large meta-analyses (Circulation 2006;113:2906). Adverse outcomes have been observed for both nonselective and COX-2 selective agents.

NSAIDS should be discontinued in patients presenting with UA/NSTEMI.

Acetaminophen is an acceptable alternative for the treatment of osteoarthritis and other musculoskeletal pain.

Table 24 Initial Medical Regimen for Unstable Angina/NSTEMI

Medications

Route

Dosage

Nitroglycerin

Sublingual

0.3-0.6 mg prn

Aerosol

0.4 mg prn

Intravenous

10-200 mcg/min

Oxygen

Nasal canula

2-4 L as needed

Morphine

Intravenous

2-4 mg prn

β-Blocker (metoprolol)

Intravenous

5 mg (3 doses)

Oral

25 mg qid

Aspirin

Oral

325 mg

Heparin

Intravenous

4,000 unit bolus, 12-14 units/kg/hr

Table 25 Antiplatelet Agents in Unstable Angina/NSTEMI

Medication

Dosage

Comments

Aspirin (ASA)

162-325 mg daily

Aspirin reduces subsequent MI and cardiac death in patients with unstable angina.

Clopidogrel (Plavix)

300-600 mg loading dose, 75 mg daily

In combination with ASA, clopidogrel (300 mg loading dose, then 75 mg/d) decreased the composite end point of cardiovascular death, MI, or stroke by 18% to 30% in patients with UA/NSTEMI (NEJM 2001;345:494; Lancet 2001;358:527; JAMA 2002;288:2411).

There may be further benefit in using a clopidogrel loading dose of 600 mg without an increased risk of bleeding in patients undergoing PCI (Circulation 2005;111:2099).

Ticlopidine (Ticlid)

250 mg bid

Prasugrel

60 mg loading dose, 10 mg daily

Prasugrel has increased antiplatelet potency compared to clopidogrel.

Prasugrel reduced the incidence of cardiovascular death, myocardial infarction, and stroke (9.9% vs. 12.1%) at the expense of increased major (2.4% vs. 1.1%) and fatal bleeding (0.4% vs. 0.1%), compared to clopidogrel (NEJM 2007; 357:2001).

Eptifibatide (Integrilin)a

180 mcg/kg IV bolus, 2 mcg/kg/mina,b

Eptifibatide reduces the risk of death or MI in patients with ACS undergoing either invasive or noninvasive therapy in combination with ASA and heparin (NEJM 1998;339:436; Circulation 2000;101:751).

Compared to abciximab and tirofiban, eptifibatide has the most consistent effects on platelet inhibition with shortest on-time and drug half-life (Circulation 2002;106:1470-1476).

Tirofiban (Aggrastat)

0.4 mcg/kg IV bolus, 0.1 mcg/kg/mina,b

Tirofiban reduces the risk of death or MI in patients with ACS undergoing either invasive or noninvasive therapy in combination with ASA and heparin (Circulation 1997; 96:1445; NEJM 1998;338: 1498; NEJM 1998;338:1488).

Abciximab (ReoPro)

0.25 mg/kg IV bolus, 10 mcg/mina,c

Abciximab reduces the risk of death or MI in patients with ACS undergoing coronary intervention (NEJM 1994;330:956; Lancet 1997;349:1429; NEJM 1997; 336:1689). It should not be used in patients in whom percutaneous intervention is not planned (Lancet 2001;357:1915).

Platelet inhibition may be reversed by platelet transfusion.

a The recommended duration of treatment is 72 to 96 hours following presentation or at least 12 hours after any percutaneous intervention.

b Infusion doses should be decreased by 50% in patients with a GFR less than 30 mL/min and avoided in patients on HD.

c Abciximab may be used in patients with ESRD, as it is not cleared by the kidney.

Table 26 Anticoagulant Medications

Medication

Dosage

Comments

Heparin (UFH)

60 units/kg IV bolus (maximum dose: 4,000 units), 12-14 units/kg/hr

Heparin therapy, when used in conjunction with ASA, has been shown to reduce the early rate of death or MI by up to 60% (JAMA 1996;276:811).

The activated partial thromboplastin time (aPTT) should be adjusted to maintain a value of 1.5-2.0 times control.

Enoxaparin (LMWH)

1 mg/kg SC bida

LMWH is at least as efficacious as UFH and may further reduce the rate of death, MI, or recurrent angina (NEJM 1997;337:447).

LMWH may increase the rate of bleeding (JAMA 2004;292:45) and cannot be reversed in the setting of refractory bleeding.

LMWH does not require monitoring for clinical effect. If cardiac catheterization is planned, then the dose should be withheld on the morning of procedure.

Fondaparinux

2.5 mg SC daily

Fondaparinux has efficacy similar to that of LMWH with possibly reduced bleeding rates (NEJM 2006;354:1464).

Bivalirudin (Angiomax)b

0.75 mg/kg IV bolus, 1.75 mg/kg/hr

When used in conjunction with ASA and clopidogrel, bivalirudin is at least as effective as the combination of ASA, UFH, clopidogrel, and GP IIb/IIIa antagonists with decreased bleeding rates (NEJM 2006;355:2203).

Monitoring is required with a goal aPTT of 1.5-2.5 times control.

a LMWH should be given at reduced dose (50%) in patients with a serum creatinine greater than 2 mg/dL or GFR less than 30 mL/min.

b Bivalirudin requires dosage adjustment in patients with a GFR less than 30 mL/min or those on hemodialysis.

Table 27 Antianginal Medications

Medication

Dosage

Comments

Nitroglycerin (NTG)

SL: 0.4 mg every 5 min

Topical: 0.5-2 in.

IV: 10-200 mcg/min

Significant antianginal effects are not seen above 200 mcg/min, but doses of up to 400 mcg/min can be used for BP control.

Nitroglycerin is contraindicated in patients who have used PDE5 inhibitors (e.g., within 24 hr of sildenafil or 48 hr of tadalafil) given the risk of severe hypotension. Appropriate timing for vardenafil dosing with nitrates is unknown and should be avoided.

Nitrates are relatively contraindicated in patients who are preload dependent, including those with severe aortic stenosis and hypertrophic obstructive cardiomyopathy.

Morphine

2-4 mg IV

IV narcotics are effective agents for relief of anginal symptoms and should be used if NTG does not provide complete relief or cannot be titrated further due to hypotension or headache.

β-Blockers

Metoprolol: 5 mg IV (3 doses)

25 mg PO qid

Bisoprolol: 10-20 mg PO daily

Carvedilol: 3.125-25 mg PO bid

Atenolol: 50-200 mg PO daily

Propranolol: 20-80 mg PO bid

Esmolol: 50-300 mcg/kg/min

Nebivolol: 5-40 mg PO daily

β-Adrenergic blockade reduces the risk of recurrent ischemia, myocardial infarction, and mortality in patients with UA/NSTEMI (J Interv Cardiol 2003;16:299).

The efficacy of β-blockade is limited by the development of cardiogenic shock. Those at risk include patients greater than 70 yr of age, SBP less than 120 mm Hg, and heart rate greater than 110 bpm or less than 60 bpm. In such cases, oral agents at reduced doses may be cautiously used (Lancet 2005;366:1622).

Calcium channel blockers

Nifedipine 30-180 mg daily

Amlodipine 5-10 mg daily

Diltiazem 30-80 mg qid

Verapamil 80-160 mg tid

Short-acting nifedipine preparations should be avoided in the absence of adequate concurrent β-blocker therapy because of increased risk of myocardial infarction and death.

Verapamil and diltiazem should be avoided in patients with evidence of severe LV dysfunction, pulmonary congestion, or AV block.

Other Nonoperative Therapies

Revascularization

The indications for PCI and CABG in patients with UA/NSTEMI are similar to those for individuals with stable angina.

Patients who are optimally managed with CABG include those with:

- Significant left main CAD

- Three-vessel disease and abnormal LV function (EF <50%)

- Two-vessel disease with a significant proximal LAD artery stenosis and abnormal LV function

- Diabetes and multivessel disease

Patients with multivessel coronary disease requiring revascularization can be treated with CABG or PCI. Patients who are treated with CABG tend to have a lower incidence of angina, less need for subsequent revascularization, but increased risk of stroke. There is no difference in the rates of cardiac death or MI between the two treatment strategies with either the use of bare metal stents (BMS) or DES. While the preferred treatment of unprotected left main disease remains CABG, however, recent data do suggest an important role for PCI (Circulation 2008;118:1146; NEJM 2009;360:961).

The decision between PCI and CABG should be based on the extent and complexity of coronary disease, medical comorbidities, and patient preference.

If there is uncertainty regarding the hemodynamic significance of a coronary lesion, fractional flow reserve (FFR) can be performed to quantify the functional severity of blood flow limitation. This modality has been shown to reduce death, recurrent MI, or revascularization compared to conventional PCI at 1 year in patients with multivessel CAD (NEJM 2009;360:213).

DES significantly reduce the rate of ISR and adverse cardiac outcomes compared to BMS (NEJM 2003;349:1315; Circulation 2003;108:788). However DES imparts an additional risk of late stent thrombosis, most notably following the discontinuation of clopidogrel therapy within 1 year following stent placement (JAMA 2007;297:159).

The management of patients following PCI is discussed in detail in the section on hypertension, dyslipidemia and stable angina.

Lifestyle/Risk Modification

Risk factor modification is addressed in detail in the section on STEMI and should include attention to smoking cessation, weight loss, exercise, control of hypertension, diabetes, and hyperlipidemia.

COMPLICATIONS

The highest rate of progression to MI or development of recurrent MI is in the first 2 months after presentation with the index episode. Beyond that time point, most patients have a clinical course similar to those with chronic stable angina.

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MONITORING/FOLLOW-UP

It is incumbent on the entire hospital staff (physicians, nurses, dietitians, pharmacists, and rehabilitation specialists) to prepare the patient for hospital discharge. The patient should be discharged on a medical regimen that takes advantage of proven methods of secondary prevention. The patient should also be provided a sublingual or spray formulation of nitroglycerin and instructed on its appropriate use.

Arrangements for follow-up care should also be established before hospital discharge.

ST-Segment Elevation Myocardial Infarction

GENERAL PRINCIPLES

STEMI is a medical emergency caused by acute occlusion of an epicardial coronary artery. Vessel occlusion is most often due to atherosclerotic plaque rupture and subsequent thrombus formation.

Compared to UA/NSTEMI, STEMI is associated with a higher in-hospital and long-term morbidity and mortality. Left untreated, the mortality rate of uncomplicated STEMI can exceed 30% and the presence of mechanical complications (papillary muscle rupture, ventricular septal defect [VSD], and free wall rupture) increases the mortality rate to 90%. Over the past few decades, there has been a dramatic improvement in short-term mortality to the current rate of 6% to 10%.

Ventricular fibrillation accounts for approximately 50% of mortality and occurs within the first hour from symptom onset.

Keys to treatment of STEMI include rapid recognition and diagnosis, coordinated mobilization of health care resources, and prompt reperfusion therapy.

Mortality is directly related to total ischemia time and restoration of coronary blood flow.

Prevention

Secondary prevention. The strategies outlined for primary prevention and the management of stable angina have also been shown to decrease the rates of repeat infarction, progression to CHF, and incidence of cardiovascular deaths in patients with known CAD (see stable angina).

DIAGNOSIS

Clinical Presentation

Clinical stratification on initial presentation

Multiple risk assessment tools have been developed to stratify patients presenting with acute STEMI into low-, intermediate-, and high-risk groups based on history, physical exam, and hemodynamic monitoring (Fig. 4).

The Killip classification system utilizes history and physical exam findings (S3 gallop, pulmonary congestion, and cardiogenic shock) to predict 30-day mortality in the absence of reperfusion therapy (Am J Cardiol 1967;20:457). In contrast, the TIMI risk score for STEMI incorporates a combination of history and physical to predict 30-day mortality in patients who receive thrombolytic therapy (Circulation 2000;102:2031). The Forrester classification system uses invasive

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hemodynamic data including cardiac index and pulmonary capillary wedge pressure (NEJM 1976;295:1356).

Figure 4. Risk indices for ST-segment elevation MI. Killip classification in acute MI. Top. TIMI risk score for STEMI (Circulation 2000;102:2031). Bottom. Killip classification system (Am J Cardiol 1967;20:457). The TIMI risk score incorporates prognosis following coronary reperfusion with thrombolytic therapy. The Killip classification system was devised before reperfusion therapy was routinely used. HTN, hypertension; BP, blood pressure.

History

Chest pain from STEMI resembles angina, but lasts longer, is more intense, and is not relieved by rest or sublingual nitroglycerin. Chest discomfort may be accompanied by dyspnea, diaphoresis, palpitations, nausea, vomiting, fatigue, and/or syncope.

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It is imperative to determine the time of symptom onset, as this is critical in determining the appropriate means of reperfusion (Table 28).

STEMI may have atypical presentations particularly in women, elderly and postoperative patients as well as those with diabetes and chronic or end-stage kidney disease. Such patients may experience atypical or no chest pain and may instead present with confusion, dyspnea, unexplained hypotension, or CHF.

If the patient has a history of previous cardiac catheterization or revascularization, it is important to obtain these records, as these can provide valuable information with respect to PCI planning, particularly in the setting of previous coronary artery bypass grafting. However, this should not delay definitive therapy.

Review absolute and relative contraindications to thrombolytic therapy (see below) and potential issues complicating primary PCI (IV contrast allergy, PVD/peripheral revascularization, renal dysfunction, CNS disease, pregnancy, and bleeding diathesis).

Inquire about recent cocaine use. In this setting, aggressive medical therapy with nitroglycerin, coronary vasodilators, and benzodiazepines should be administered before reperfusion therapy is considered.

Table 28 Key Information in the Patient Presenting with STEMI

History and Physical Exam

Laboratory Values

Records

Inquire about the exact time of chest pain onset

Complete blood cell count

Prior ECGs

Consider other etiologies of chest pain with ST-segment elevation (i.e., aortic dissection, cocaine use)

Basic chemistry panel

Last cardiac catheterization

Identify absolute and relative contraindications to PCI and thrombolysis

PTT, PT and INR

CABG operative report

Evaluate for signs of heart failure, mechanical complications of MI, aortic dissection, and neurologic disease

Cardiac enzymes

Prior echocardiogram

Physical Examination

Physical examination should be directed at identifying hemodynamic instability, pulmonary congestion, mechanical complications of MI, and other causes of acute chest discomfort.

The identification of a new systolic murmur may suggest the presence of ischemic mitral regurgitation (MR) or a VSD.

A limited neurologic exam to detect baseline cognitive and motor deficits and a vascular examination (lower extremity pulses and bruits) will aid in determining candidacy for reperfusion treatment.

Cardiogenic shock due to right ventricular myocardial infarction (RVMI) may be clinically suspected by the presence of hypotension, elevated jugular venous pressure,

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and absence of pulmonary congestion. While RVMI may be seen in isolation, it more commonly complicates inferior/posterior MI.

Bilateral arm BPs should be obtained to assess for the presence of aortic dissection.

Diagnostic Criteria

STEMI requires the presence of at least two of the following criteria:

History of prolonged chest discomfort or anginal equivalent (30 minutes)

Presence of ≥1 mm ST-segment elevation in two consecutive ECG leads or new LBBB

Presence of elevated cardiac biomarkers

Diagnostic Testing

Laboratories

Blood samples should be sent for cardiac enzymes (Troponin, CK-MB), complete blood cell count, coagulation studies (PTT, prothrombin time [PT], international normalized ratio [INR]), creatinine, electrolytes including magnesium, and type and screen. A fasting lipid profile should be obtained in all patients with STEMI for secondary prevention.

Initial cardiac enzymes (including high-sensitivity troponin assays) may be normal, depending upon the time in relation to symptom onset. In general, cardiac enzymes should have little role in the initial decision making process and awaiting these studies may lead to unnecessary delays in delivering therapy.

CK-MB can be used to confirm that myocardial injury occurred within the previous 48 hours, as troponin levels may remain elevated for several days after MI. CK-MB is also useful to detect periprocedural infarctions.

The risk of subsequent cardiac death is directly proportional to the increase in cardiac-specific troponins, even when CK-MB levels are not elevated. Cardiac enzymes should be measured daily until the peak level has been reached to determine the extent of myocardial damage.

Routine use of cardiac noninvasive imaging is not recommended for the initial diagnosis of STEMI. When the diagnosis is in question, a transthoracic echocardiogram (TTE) can be performed to document regional wall motion abnormalities. If not adequately evaluated by TTE, a transesophageal echocardiogram (TEE) can be obtained to assess for acute complications of MI and presence of aortic dissection.

A portable chest radiograph is useful to assess for pulmonary edema and evaluate for other causes of chest pain including aortic dissection. Importantly, a normal mediastinal width does not exclude aortic dissection, especially if clinically suspected.

Electrocardiography

The ECG is paramount to the diagnosis of STEMI and should be obtained within 5 minutes of presentation. If the diagnosis of STEMI is in doubt, serial ECGs may help elucidate the diagnosis. Classic findings include (Table 29):

T waves. Peaked upright T waves may be the first ECG manifestation of myocardial injury.

ST-segment changes

Convex ST-segment elevation ≥ 1 mm in two consecutive leads with peaked or inverted T waves is usually indicative of myocardial injury and correlates with the territory of injured myocardium (Fig. 8).

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Posterior wall MI is recognized by ST-segment depression in leads V1 to V3, ST-segment elevation in V7 to V9 and is treated as a STEMI.

RVMI is diagnosed with ST-segment elevation in lead V4R.

ECG criteria for ischemic changes in patients with preexisting LBBB or RV-pacing can be found in Table 30.

Qwaves. Development of new pathologic Q waves (>40 milliseconds) is considered diagnostic for MI, but may occur in patients with prolonged ischemia.

A new LBBB suggests anterior wall injury.

Infarction of the left circumflex territory may be electrocardiographically silent.

The presence of reciprocal ST-segment depression opposite of the infarct territory increases the specificity for acute MI.

ECG changes that mimic MI. ST-segment elevation and Q waves may result from numerous etiologies other than acute MI including prior MI with aneurysm formation, aortic dissection, LV hypertrophy, pericarditis, myocarditis, and pulmonary embolism (Table 31). It is critical to obtain prior ECGs to clarify the diagnosis.

Table 29 ECG-Based Anatomic Distribution

ST Elevation

Myocardial Territory

Coronary Artery

V1-V6 or LBBB

Anterior and septal walls

Proximal LAD or left main

V1-V2

Septum

Proximal LAD or septal branch

V2-V4

Anterior wall

LAD

V5-V6

Lateral wall

LCX

II, III, aVF

Inferior wall

RCA or LCX

I, aVL

High lateral wall

Diagonal or proximal LCX

LBBB, left bundle branch block; LAD, left anterior descending artery; LCX, left circumflex artery; RCA, right coronary artery.

TREATMENT

Acute management. Prompt treatment should be initiated as soon as the diagnosis is suspected, as mortality and subsequent HF are directly related to ischemia time (Fig. 5). All medical centers should utilize an AHA/ACC guideline-based STEMI protocol. Centers that are not primary PCI capable should have protocols in place to

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meet accepted time to therapy guidelines for either administration of thrombolytic therapy with subsequent transfer or rapid transfer to a primary PCI-capable facility.

Before presentation to the hospital. The general public should be informed of the signs and symptoms consistent with an acute MI that should lead them to seek urgent medical care. Availability of “911” access and emergency medical services facilitates delivery of patients to emergency medical care.

In the emergency department, an acute MI protocol should be activated that includes a targeted clinical examination and a 12-lead ECG completed within 10 minutes of arrival.

Immediate management. The goal of immediate management in patients with STEMI is to identify candidates for reperfusion therapy. The goal is a door-to-needle time of <30 minutes or door-to-balloon time of <90 minutes. Other key priorities include relief of ischemic pain as well as recognition and treatment of hypotension, pulmonary edema, and arrhythmia.

General measures include continuous BP, pulse oximetry, and telemetry monitoring.

Supplemental oxygen should be administered if saturations are <90%. If necessary, institution of mechanical ventilation decreases the work of breathing and reduces myocardial oxygen demand.

Two peripheral IV catheters should be inserted upon arrival.

Serial ECGs should be obtained for patients who do not have ST-segment elevation on the initial ECG, but experience ongoing chest discomfort as they may demonstrate evolving ST-segment elevation.

Table 30 Criteria for ST-segment Elevation for Prior LBBB or RV-paced Rhythm

ECG change

ST-segment elevation greater than 1 mm in the presence of a positive QRS complex (concordant with the QRS)

ST-segment elevation greater than 5 mm in the presence of a negative QRS complex (disconcordant with the QRS)

ST-segment depression greater than 1 mm in V1-V3.

Sgarbossa's (GUSTO) criteria: Am J Cardiol 1996;77:423; NEJM 1996;334:481; PACE 2001; 24:1289.

Table 31 Differential Diagnosis of ST-Segment Elevation

Cardiac Etiologies

Other Etiologies

Prior MI with aneurysm formation

Pulmonary embolism

Aortic dissection with coronary involvement

Hyperkalemia

Pericarditis

Myocarditis

LV hypertrophy or aortic stenosis (with straina)

Hypertrophic cardiomyopathy

Coronary vasospasm (cocaine, Prinzmetal angina)

Early repolarization (normal variant)

Brugada syndrome

a Strain may occur in numerous settings including systemic hypertension, hypotension, tachycardia, exercise, and sepsis.

Medications

Upstream medical therapy should include administration of antiplatelet and anticoagulant medications as well as agents that reduce myocardial ischemia (Table 32).

Aspirin (ASA) should be given immediately to all patients with suspected acute MI. ASA treatment resulted in relative reduction in cardiovascular mortality by 23% and the incidence of nonfatal MI by 49% (Lancet 1988;2:349).

Clopidogrel reduces mortality, reinfarction, and acute stent thrombosis without an increase in serious bleeding or intracranial hemorrhage when given in conjunction

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with thrombolytic therapy or PCI (Lancet 2005;366:1607; NEJM 2005;352:1179; JAMA 2005;294:1224). Clopidogrel can be given as an alternative to aspirin in the setting of true aspirin allergy (anaphylaxis). Subsequent allergy consultation for aspirin desensitization should be obtained as ASA and clopidogrel treatment is superior to either agent alone.

Prasugrel may be used as an alternative to clopidogrel. In patients who presented with STEMI, prasugrel decreased adverse cardiac outcomes without an increase in major bleeding events compared to clopidogrel (300 mg loading dose, 75 mg maintenance dose) (NEJM 2007;357:2002; Lancet 2009;373:723).

Glycoprotein (GP) IIb/IIIa inhibitors have shown limited efficacy and increased bleeding rates when used in conjunction with ASA and clopidogrel prior to primary

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PCI (see facilitated PCI). However, it may be reasonable to use GP IIb/IIIa inhibitors as an alternative to clopidogrel, particularly in patients who present with acute complications of MI requiring surgery (ischemic MR, ruptured papillary muscle, or VSD).

Anticoagulant therapy (UFH, LMWH, or bivalirudin) should be initiated in all patients with acute MI regardless of the choice of PCI, thrombolytic, or medical therapy.

LMWH (enoxaparin) is an alternative to UFH with more predictable kinetics and easier route of administration that has shown efficacy in conjunction with thrombolysis and PCI (Lancet 2001;358:605; NEJM 2006;354:1477; JACC 2007;49:2238). UFH is preferred during PCI as real-time therapeutic monitoring of LWMH in the catheterization laboratory is often not possible.

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Bivalirudin should be given to patients with HIT and has equivalent efficacy to UFH with respect to overall mortality when given in combination with ASA and clopidogrel in patients undergoing primary PCI. Bivalirudin reduced bleeding rates at the expense of an increased frequency of acute stent thrombosis (NEJM 2008;358:2218; Lancet 2009;374:1149).

UFH or LMWH should be administered to patients receiving selective fibrinolytic agents (alteplase, reteplase, or tenecteplase). UFH has been shown to increase bleeding without improving mortality in patients who receive streptokinase.

Nitroglycerin should be administered to patients with ischemic chest pain. Nitroglycerin should either be avoided or used with caution in patients with:

Hypotension (SBP < 90 mm Hg)

RVMI

HR greater than 100 or less than 50 bpm

Documented use of phosphodiesterase inhibitors

Morphine (2 to 4 mg IV) can be used for refractory chest pain that is not responsive to nitroglycerin. Adequate analgesia decreases levels of circulating catecholamines and reduces myocardial oxygen consumption.

β-Adrenergic blockade improves myocardial ischemia, limits infarct size, and reduces major adverse cardiac events including mortality, recurrent ischemia, and malignant arrhythmias. IV β-blockers can increase mortality in patients with HF, cardiogenic shock (Killip II or greater), age older than 70 years, SBP less than 120 mm Hg, HR greater than 110 or less than 60 bpm (Lancet 2005;366:1622). Oral β-blockers may be used with caution in select patients.

Acute coronary reperfusion

The majority of patients who suffer an acute STEMI have thrombotic occlusion of the infarct-related coronary artery. Early restoration of coronary perfusion limits infarct size, preserves LV function, and reduces mortality.

All patients who present with a STEMI within 12 to 24 hours of symptom onset should be considered for immediate reperfusion therapy.

Unless spontaneous resolution of ischemia occurs (as determined by resolution of chest discomfort and normalization of ST elevation), the choice of reperfusion strategy includes thrombolysis, primary PCI, or emergent CABG (Fig. 6).

The choice of reperfusion therapy should almost be considered of secondary importance to the overall goal of achieving reperfusion in a timely fashion as the morbidity and mortality associated with an acute MI are linearly related to the time to treatment.

In general, primary PCI is the preferred reperfusion strategy when available within 90 minutes of medical contact (including transfer to a PCI-capable facility). If cardiac catheterization is not readily available, thrombolytic therapy should be administered within 30 minutes of medical contact.

PCI is preferred over thrombolysis in patients who:

- Are <75 years of age and present with cardiogenic shock within 36 hours of MI and PCI can be performed within 18 hours of shock

- Have a contraindication to fibrinolytic therapy

- Are at high risk of death or development of CHF

- Underwent recent PCI or prior CABG

Thrombolysis may be preferred if patients are presenting to the hospital within the first 2 hours of symptom onset.

Primary PCI is the preferred reperfusion strategy when performed in a timely fashion at an appropriate facility. Compared to thrombolytic therapy, PCI offers

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superior vessel patency and improved survival regardless of lesion location or patient age (NEJM 1997;336:1621; Lancet 2003;361:13).

Primary PCI should be considered if an available catheterization facility can provide a door-to-balloon time of less than 90 minutes. Optimally, operators should perform greater than 75 PCIs per year at experienced centers with a volume that exceeds 200 PCIs per year.

Patients who present to a facility where cardiac catheterization is not available should be immediately transferred to a PCI-capable center with an estimated total door-to-balloon time of less than 90 minutes. In this setting, primary

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PCI significantly lowered the incidence of death, MI, or stroke compared to on-site thrombolysis (NEJM 2003;249:733; JACC 2002;39:1713; Eur Heart J 2000;21:823). If the estimated transfer time will exceed a total door-to-balloon time of 90 minutes, on-site thrombolysis should be performed (see below).

PCI is also indicated in patients who present with cardiogenic shock, refractory arrhythmias, have contraindications to thrombolytic therapy, or if the diagnosis is uncertain.

Treatment is optimal when the angioplasty is performed within 12 hours of symptom onset and may be effective beyond that point if symptoms persist.

Additional advantages of primary PCI include immediate assessment of coronary anatomy, atherosclerotic disease burden, and LV function.

If the patient has multivessel coronary disease, the appropriateness and timing of complete revascularization should be determined after the infarct-related artery is opened and the patient stabilized.

- If the functional significance of coronary lesions is not readily apparent, an invasive (FFR) or noninvasive (stress testing) assessment should be undertaken.

- Complete revascularization is best performed in a staged manner to minimize contrast-mediated renal toxicity.

Coronary stenting is superior to balloon angioplasty alone and reduces the rates of target vessel revascularization (NEJM 1999;341:1949; NEJM 2002;346:957). DES further reduce the need for target vessel revascularization without increasing the incidence of stent thrombosis (Circulation 2009;120:964; JACC 2008;51:618; JAMA 2008;299:1788).

Abciximab infusion at the time of PCI should be routinely used as it reduces the rate of death, MI, and urgent revascularization by approximately 50% (Circulation 1998;98:734; NEJM 2001;344:1895; JACC2003;42:1879). Recommended anticoagulation strategies for PCI are shown in Figure 7.

- Eptifibatide and tirofiban may have similar efficacy to abciximab (Am J Cardiol 2004;94:35; JAMA 2008;299:1788; JACC 2008;51:529).

- Bivalirudin is an acceptable alternative to the use of combined heparin and GP IIb/IIIa inhibitor during PCI with lower bleeding rates (NEJM 2008;358:2218 JAMA 2003;19:853).

Facilitated PCI, a strategy of reduced dose of GP IIb/IIIa inhibitors and/or thrombolytic agent prior to PCI, should not be routinely employed as it does not improve efficacy and significantly increases bleeding rates (Lancet 2006;367:569; NEJM 2008;358:2205; Lancet 2006;367:579).

Thrombolytic therapy offers the advantages of availability and rapid administration. The primary disadvantage of thrombolytic therapy is the risk of intracranial hemorrhage, uncertainty of whether normal coronary flow has been restored, and reocclusion of the infarct-related artery.

Thrombolytic therapy is most effective if given within 12 hours of the symptom onset with a pooled relative mortality reduction of 18% (Lancet 1994;343:311; Lancet 1987;2:871). Beyond 12 hours, thrombolysis yields little benefit.

Thrombolytic therapy is not indicated for patients with resolved chest pain or those with ST-segment depression.

Absolute and relative contraindications to thrombolytic therapy are listed in Table 33.

Multiple thrombolytic agents are available and are classified into two groups based on their selectivity for fibrin substrates. Fibrin-selective agents include recombinant tissue plasminogen activator (rt-PA), reteplase (r-PA), and

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tenecteplase (TNK-tPA). Streptokinase is the only nonselective agent in use. Further details and dosing information can be found in Table 34.

- The choice of thrombolytic agent is guided by considerations of efficacy, bleeding risk, availability, ease of administration, and cost. Compared with streptokinase, rt-PA is associated with a slightly greater risk of intracranial hemorrhage but offers the net clinical benefit of additional 10 lives saved per 1,000 patients treated (NEJM 1993;329:673).

- Fibrin-selective agents should be used in combination with anticoagulant therapy (UFH, LMWH, fondaparinux, or bivalirudin). Recent studies have demonstrated that LMWH and fondaparinux may be superior to UFH (Lancet 2001;358:605; Circulation 2002;105:1642; NEJM 2006;354:1477; JAMA 2006;295:1519). Addition of UFH to streptokinase does not improve outcomes (NEJM 1993;329:673).

The therapeutic efficacy of thrombolytic treatment can be monitored by clinical response (resolution of chest pain), improvement in ST-segment elevation, or by the presence of accelerated idioventricular rhythm.

- Thrombolytic therapy does not achieve coronary artery patency in 30% of patients. In contrast, primary PCI results in restoration of normal coronary flow (TIMI 3) in greater than 95% of cases.

Individuals with persistent angina or persistent ischemic changes on the ECG (<50% reduction in ST-segment elevation) 60 to 90 minutes after the initiation of thrombolytic therapy should be considered for urgent coronary angiography and PCI (rescue PCI).

- Rescue PCI reduces the incidence of death, reinfarction, and HF by nearly 50% (Circulation 1994;90:2280; NEJM 2005;353:2758).

- Routine coronary angiography within 24 hours of thrombolysis has reduced adverse cardiac events compared to rescue PCI (Lancet 2004;264:1045). Routine PCI has also proved beneficial for patients who receive thrombolysis as an initial therapy and are subsequently transferred to a PCI-capable facility (Lancet 2008;371:559). This strategy should be differentiated from facilitated PCI where thrombolytic agents are administered immediately before primary PCI.

The most common complication of thrombolytic therapy is bleeding. Intracranial hemorrhage occurs in 0.7% to 0.9% of cases and may result in death or permanent neurologic defects.

- The risk of intracranial hemorrhage is increased twofold in patients older than 75 years, less than 70 kg, on anticoagulation therapy (Coumadin), or with severe hypertension (BP > 170/90).

- Any patient who experiences a sudden change in neurologic status should undergo urgent head CT and all anticoagulant and thrombolytic therapies discontinued. Fresh frozen plasma should be given to patients with intracerebral hemorrhage. Cryoprecipitate may also be used to replenish fibrinogen and factor VIII levels. Platelet transfusions can be useful in patients with markedly prolonged bleeding times. Neurologic and neurosurgical consultation should be obtained immediately.

- Major bleeding complications that require blood transfusion occur in approximately 10% of patients.

- Venipuncture should be limited and arterial puncture avoided in patients treated with thrombolytic therapy for 24 hours after the initiation of treatment.

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Emergency CABG is a high-risk procedure that should be considered only if the patient has severe left main disease or refractory ischemia in the setting of failed PCI or coronary anatomy that is not amenable to PCI. Emergency surgery should also be considered for patients with acute mechanical complications of MI including papillary muscle rupture, severe ischemic MR, VSD, ventricular aneurysm formation in the setting of intractable ventricular arrhythmias, or ventricular free wall rupture.

Figure 5. The benefit of coronary reperfusion is inversely related to ischemia time. Top. Graphic representation of mortality benefit of coronary reperfusion as a function of ischemia time. (Adapted from JAMA 2005;293:979.) Bottom. Recommended timeline of events following chest pain onset as a according to ACC/AHA guidelines (Circulation 2008;117:296).

Table 32 Upstream Medical Therapy

Medication

Dosage

Comments

Aspirin (ASA)

162-325 mg

Nonenteric coated formulations (chewed or crushed) given orally or rectally facilitate rapid drug absorption and platelet inhibition.

Clopidogrel

300-600 mg loading dose, 75-150 mg daily

600 mg loading dose followed by 7 d of 150 mg maintenance dose may reduce the incidence of stent thrombosis and MI compared to the standard 300 mg loading dose and 75 mg maintenance dose.

Caution should be used in the elderly as clinical trials validating clopidogrel use in STEMI either did not include elderly patients or did not use a loading dose.

Prasugrel

60 mg loading dose 10 mg daily

Compared to clopidogrel, prasugrel is a quicker acting and more potent antiplatelet agent with improved efficacy, but did significantly increase CABG bleeding rates.

Prasugrel should not be used in patients greater than 75 yr old, less than 60 kg, or with a history of stroke/TIA.

Unfractionated heparin (UFH)

60 units/kg IV bolus, 12 units/kg/hr

UFH should be given to all patients undergoing PCI and those receiving thrombolytics with the exception of streptokinase.

The maximum IV bolus is 4,000 units.

Enoxaparin (LMWH)

30 mg IV bolus, 1 mg/kg SC bid

Patients greater than 75 yr of age should not be given a loading dose and receive 0.75 mg SC bid.

An additional loading dose of 0.3 mg/kg should be given if the last dose of LMWH was more than 8 hr prior to PCI. The use of LMWH is only validated in thrombolysis and rescue PCI.

Bivalirudin

0.75 mg/kg IV bolus, 1.75 mg/kg/hr

Bivalirudin has been validated in patients undergoing PCI and has not been studies in conjunction with thrombolysis.

Patients who received a heparin bolus prior to bivalirudin had a lower incidence of stent thrombosis than those who only received bivalirudin.

Fondaparinux

2.5 mg IV bolus, 2.5 mg SC daily

Shown to be superior to UFH when used during thrombolysis with decreased bleeding rates.

Fondaparinux increases the risk of catheter thrombosis when used during PCI (JAMA 2006;295:1519).

Nitroglycerin

0.4 mg SL or aerosol infusion: 10-200 mcg/min

Sublingual or aerosol nitroglycerin can be given every 5 min for a total of three doses in the absence of hypotension. IV nitroglycerin can be used for uncontrolled chest discomfort.

Metoprolol

5 mg IV (3 doses), 25 mg PO qid

β-Blockers should also be avoided in patients with evidence of heart failure, hemodynamic instability, marked first-degree AV block, advanced heart block, and bronchospasm.

Figure 6. Strategies for coronary reperfusion and risk assessment. 1Prasugrel may be used in place of clopidogrel in patients undergoing PCI. 2UFH may be used with either PCI or thrombolytic therapy, while bivalirudin has only been studied with PCI and LMWH has only been validated for thrombolytic therapy and rescue PCI. 3Patients who do not experience chest pain relief or ST-segment normalization 60 to 90 minutes following thrombolysis should undergo rescue PCI. 4Signs of successful reperfusion include chest pain relief, 50% reduction in ST-segment elevation and idioventricular rhythm. ASA, aspirin; UFH, unfractionated heparin; LMWH, low-molecular-weight heparin; NTG, nitroglycerin; PCI, percutaneous coronary intervention; CABG, coronary artery bypass graft.

Figure 7. Recommended strategies for upstream therapy prior to PCI. 1Prasugrel may be used in place of clopidogrel in patients undergoing PCI. GP IIb/IIIa inhibitors may be used instead of clopidogrel in patients who present with mechanical complications of MI and require urgent cardiac surgery. 2In comparison to UFH + GP IIb/IIIa inhibitor, bivalirudin improves mortality and decreases bleeding in patients presenting with STEMI. A heparin bolus should be given prior to bivalirudin to decrease the rate of stent thrombosis (NEJM2008;358:2218). 3LMWH has only been studied in rescue PCI and has not been validated for primary PCI (NEJM 2006;354:1477). ASA, aspirin; UFH, unfractionated heparin; LMWH, low-molecular-weight heparin; NTG, nitroglycerin; PCI, percutaneous coronary intervention.

Table 33 Contraindications to Thrombolytic Therapy

Absolute Contraindications

Relative Contraindications

History of intracranial hemorrhage or hemorrhagic stroke

Prior ischemic stroke more than 3 mo ago

Ischemic stroke within 3 mo

Allergy or previous use of streptokinase (greater than 5 d ago)a

Known structural cerebrovascular lesion (AVMs, aneurysms, tumor)

Closed head injury within 3 mo

Recent internal bleeding (2-4 wk)

Aortic dissection

Prolonged/traumatic CPR more than 10 min

Severe uncontrolled hypertension (SBP > 180 mm Hg, DBP > 110 mm Hg)

Major surgery within 3 wk

Active peptic ulcer disease

Active bleeding or bleeding diathesis

Noncompressible vascular punctures

Acute pericarditis

Severe menstrual bleeding

History of intraocular bleeding

Pregnancy

AVM, arteriovenous malformation; CPR, cardiopulmonary resuscitation; DBP, diastolic blood pressure; SBP, systolic blood pressure.

a Thrombolytics other than streptokinase may be used.

Table 34 Thrombolytic Agents

Medication

Dosage

Comments

Streptokinase (SK)

1.5 million units IV over 60 min

Produces a generalized fibrinolytic state (not clot specific).

SK reduces mortality following STEMI: 18% relative risk reduction and 2% absolute risk reduction (Lancet 1987;2:871).

Allergic reactions including skin rashes, fever, and anaphylaxis may be seen in 1-2% of patients. Isolated hypotension occurs in 10% of patients and usually responds to volume expansion.

Because of the development of antibodies, patients who were previously treated with streptokinase should be given an alternate thrombolytic agent.

Recombinant tissue plasminogen activator (rt-PA)

15 mg IV bolus

0.75 mg/kg over 30 min (maximum 50 mg)

0.50 mg/kg over 60 min (maximum 35 mg)

Fibrin selective agent with improved clot specificity compared to SK.

Does not cause allergic reactions or hypotension.

Mortality benefit compared to SK at the expense of an increased risk of intracranial hemorrhage (NEJM 1993;329:673)

Reteplase (r-PA)

Two 10-unit IV boluses administered 30 min apart

Fibrin selective agent with a longer half-life but reduced clot specificity compared to rt-PA.

Mortality benefit equivalent to that of rt-PA (NEJM 1997;337:1118).

Tenecteplase (TNK-tPA)

0.50 mg/kg IV bolus (total dose 30-50 mg)

Genetically engineered variant of rt-PA with slower plasma clearance, improved fibrin specificity, and higher resistance to plasminogen activator inhibitor-1 (PAI-1).

Mortality benefit equivalent to that of rt-PA with reduced bleeding rates (Lancet 1999;354:716).

Monitoring is required with a goal aPTT of 1.5-2.5 times control.

Peri-infarct Management

The coronary care unit (CCU) was the first major advance in the modern era of treatment of acute MI. The majority of patients benefit from the specialized training of the nursing and support staff in the CCU. Most patients with acute MI should be observed for 24 to 48 hours in the CCU.

Bedrest is appropriate intermediate care for the first 24 hours after presentation with an acute MI. After 24 hours, clinically stable patients can progressively advance their activity as tolerated.

Patients should have continuous telemetry monitoring to detect for recurrent ischemia and arrhythmias. Daily evaluation should include assessment for recurrent chest discomfort and HF symptoms, physical exam focusing on new murmurs and evidence of HF, and routine ECGs.

A baseline echocardiogram should be obtained to document ejection fraction, wall motion abnormalities, valvular lesions, and presence of ventricular thrombus.

Hemodynamic monitoring may be useful to optimize medical therapy in unstable patients (see below).

Cardiac pacing may be required in the setting of an acute MI. Rhythm disturbance may be transient in nature, in which case temporary pacing is sufficient until a stable rhythm returns (see below).

Post-MI Medical Therapy

Aspirin is the preferred antiplatelet agent after MI and should be used indefinitely. Doses of 75 to 325 mg/d have been shown to reduce the risk of recurrent MI, stroke, and cardiac death.

Clopidogrel (75 mg/d) or Prasugrel (10 mg/d) should be given for a minimum of 1 month in patients who receive a BMS and for at least 1 year in patients who receive a DES.

β-Blockers confer a mortality benefit following acute MI. Treatment should begin as soon as possible (preferably within the first 24 hours) and continued indefinitely.

ACE inhibitors provide a reduction in short-term mortality and incidence of CHF and recurrent MI when initiated within the first 24 hours of an acute MI (Lancet 1994;343:1115; Lancet 1995;345:669).

Patients with ejection fraction less than 40%, large anterior MI, and prior MI derive the most benefit from ACE-inhibitor therapy.

Therapy may be initiated with captopril and titrated as BP permits. Conversion to a more long-acting agent is appropriate prior to discharge.

Contraindications include hypotension, acute renal failure, bilateral renal artery stenosis, and hyperkalemia. Care must be taken to avoid hypotension.

Angiotensin II receptor blockers can be used in patients who are intolerant of ACE inhibitors with equivalent efficacy.

HMG-CoA reductase inhibitors should be started in all patients in the absence of contraindications. Several trials have shown the benefit of early and aggressive use of

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statins following AMI. The goal is at least 50% reduction in LDL or LDL less than 70 mg/dL.

Aldosterone receptor antagonists (Aldactone and eplerenone) have shown benefit in post-MI patients with LV ejection fraction of less than 40% (NEJM1999;341:709; NEJM 2003;348:1309). Caution should be used in patients with hyperkalemia and renal insufficiency.

SPECIAL CONSIDERATIONS

Risk assessment

Patients who present greater than 24 hours after symptom onset and those who receive thrombolysis or medical therapy alone should undergo further risk assessment. Patients may be evaluated using either a noninvasive (stress testing) or invasive (coronary angiography) strategy.

Stress testing can be used to determine prognosis, residual ischemia, and functional capacity.

A submaximal exercise stress test can be performed as early as 4 to 6 days following MI. Pharmacologic stress testing (preferably nuclear perfusion imaging) may also be used and is optimal for evaluating ischemic burden.

Alternatively, stress testing can be performed after hospital discharge (2 to 6 weeks) for low-risk patients.

Coronary angiography should be performed in patients with limiting angina, significant ischemic burden, and those with poor functional capacity.

Cardiac catheterization without prior noninvasive assessment is an alternative approach for high-risk individuals who presented greater than 24 hours after symptom onset or those managed medically. At the time of catheterization, decisions on revascularization should be made based on the patient's anatomy, ventricular function, and clinical status.

Recent studies have failed to show any benefit of opening totally occluded arteries greater than 3 days following acute MI in clinically stable patients (NEJM 2006;355:2395-2407). In this population, assessment of myocardial viability should be performed prior to PCI.

Angioplasty of a totally occluded infarct-related artery may be considered in clinically unstable patients, those with rest angina, NYHA class III-IV HF, or those with multivessel disease.

Patients treated medically who experience complications of MI, including recurrent angina/ischemia, HF, significant ventricular arrhythmia, or a mechanical complication of the MI, should proceed directly to coronary angiography to define their anatomy and offer an appropriate revascularization strategy.

Special clinical situations

RVMI is seen in approximately 50% of patients with an acute inferior MI. Roughly half of these patients have hemodynamic compromise as a result of right ventricular involvement.

Clinical signs may include hypotension, cardiogenic shock, elevated jugular venous pulsation, Kussmaul sign (an increase in jugular venous pressures with inspiration), and right-sided third or fourth heart sounds. The lung fields are often clear in the absence of a large inferior infarct or MR.

Right precordial ECG leads should be obtained and analyzed for ST elevation (V4R is the most sensitive and specific lead and is transient).

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LV filling pressures are typically normal or decreased, the right atrial pressures are elevated (>10 mm Hg), and the cardiac index is depressed. In some patients, elevated right atrial pressures may not be evident until IV fluids are administered.

Initial therapy is intravenous fluids. If hypotension persists, inotropic support with dobutamine and/or an intra-aortic balloon pump (IABP) may be necessary. Invasive hemodynamic monitoring is critical in the hypotensive patient as it guides volume status and the need for inotropic and mechanical support.

In patients with heart block and AV dyssynchrony, sequential AV pacing may have a marked beneficial effect.

ISR and stent thrombosis are disease entities unique to patients who have previously undergone coronary angioplasty. Risk factors for ISR and stent thrombosis can be found in Table 35.

ISR is a result of intimal hyperplasia and occurs within 6 to 9 months following balloon angioplasty and stent deployment. Progressive exertional angina is the typical presenting symptom. Prior to BMS, the incidence of target lesion restenosis 1 year following balloon angioplasty was 35% to 40%. BMS placement reduced the rate of angiographic restenosis to 20% to 30% and DES have further reduced the 1-year restenosis rate to 3% to 5%.

- DES placement is the treatment of choice for ISR. Several DES systems are available including paclitaxel (TAXUS), sirolimus (CYPHER), and everolimus (Xience) eluting stents. The TAXUS and CYPHER stents are the best studied and significantly reduce ISR rates (NEJM 2002;346:1773; NEJM 2003;349:1315; JAMA 2005;294:1215), with the CYPHER stent producing the lowest rates of lumen loss (JAMA 2006;295:895; Circulation 2006;114:2148). Early studies with the Xience stent have demonstrated improved results compared to the TAXUS stent (JAMA 2008;299:1903; Circulation 2009;119:680).

- Other proposed treatments for ISR including rotational atherectomy and brachytherapy produce inferior results compared to DES placement, and in the case of brachytherapy increase the risk of stent thrombosis (JAMA 2006;295: 1264; JAMA 2006;295:1253).

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Stent thrombosis occurs with BMS or DES, and is due to poor endothelial repair. Stent thrombosis commonly presents either as an ACS or as sudden cardiac death. The etiology of stent thrombosis is based on the time from prior coronary intervention (JAMA 2005;293:2126; JACC 2009;53:1399).

- Acute stent thrombosis occurs within 24 hours and is due to mechanical procedural complications as well as inadequate anticoagulation and antiplatelet therapies.

- Subacute stent thrombosis (24 hours to 30 days) is a consequence of inadequate platelet inhibition and mechanical stent complications. Cessation of clopidogrel therapy during this time yields a 30- to 100-fold risk of stent thrombosis.

- Late (30 days to 1 year) and very late (greater than 1 year) stent thrombosis occur principally with DES and are associated with clopidogrel cessation (fourto sixfold increased risk) and resistance.

- Given the high mortality rate, the best treatment for stent thrombosis is prevention. In general, PCI with thrombus aspiration and repeat stent deployment is recommended. Screening for clopidogrel resistance and initiation of more potent antiplatelet regimens such as prasugrel or clopidogrel 150 mg in combination with cilostazol is warranted (JACC 2005;46:1833; Circulation 2009;119:3207).

Ischemic MR is a poor prognostic indicator following MI that most often presents with HF. It is associated with posterior infarcts and resultant posterior papillary muscle involvement. The presence of MR following MI significantly increases mortality (Ann Intern Med 1992;117:10; Am J Med 2006;119:103).

The mechanism of acute MR includes papillary muscle dysfunction or leaflet tethering due to posterior wall akinesis.

Progressive MR following MI may develop as a result of LV chamber dilation, apical remodeling, or posterior wall dyskinesis. These changes lead to leaflet tethering or mitral annular dilation.

Echocardiography is the diagnostic modality of choice. Ischemic MR is not always readily identified on physical exam and may have unusual characteristics due to the posteriorly directed regurgitant jet. TEE may be required to access the severity and mechanism of MR.

Initial treatment involves aggressive afterload reduction and revascularization. Stable patients should receive a trial of medical therapy and undergo surgery only if they fail to improve. Early surgical intervention is warranted for patients with severe ischemic MR and HF as well as those who are unlikely to benefit from revascularization.

STEMI in the setting of recent cocaine use presents a unique and challenging management situation (Circulation 2008;117:1897-1907). ST elevation can result from myocardial ischemia due to coronary vasospasm, in situ thrombus formation, and/or increased myocardial oxygen demand. The common pathophysiology is excessive stimulation of α- and β-adrenergic receptors. Chest pain due to cocaine use usually occurs within 3 hours, but may be seen several days following use.

Oxygen, aspirin, and heparin (UFH or LMWH) should be administered to all patients with cocaine-associated STEMI.

Nitrates should be used preferentially to treat vasospasm. Additionally, benzodiazepines may confer additional relief by decreasing sympathetic tone.

Selective β1-adrenergic blockers are contraindicated due to the potential for unopposed α-adrenergic activity.

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Phentolamine (α-adrenergic antagonist) and calcium channel blockers may reverse coronary vasospasm and are recommended as second-line agents.

The use of reperfusion therapy is controversial and should be reserved for those patients whose symptoms persist despite initial medical therapy.

- Primary PCI is the preferred approach for the patient with persistent symptoms and ECG changes despite aggressive medical therapy. It is important to note that coronary angiography and intervention carry a significant risk of worsening vasospasm.

- Fibrinolytic therapy should be reserved for patients who are clearly having a STEMI who cannot undergo PCI.

Table 35 Risk Factors for ISR and Stent Thrombosis

ISR

Stent Thrombosis

Diabetes

Clopidogrel discontinuation

Chronic kidney disease

Clopidogrel resistance

Prior restenosis

Diabetes

Prior stent placed in the setting of ACS

Chronic kidney disease

Small luminal diameter (<2.5 mm)

Malignancy

Long lesion length

Prior brachytherapy

Proximal LAD lesion

Small luminal diameter (<3 mm)

Saphenous vein graft lesion

Long lesion length

Residual stenosis following prior intervention

Bifurcation lesion

Margin dissection

Incomplete wall apposition

Overlapping stents

ISR, in-stent restenosis; ACS, acute coronary syndrome; LAD, left anterior descending artery.

COMPLICATIONS

Complications following acute MI

Myocardial damage predisposes the patient to several potential adverse consequences and complications that should be considered if the patient experiences new clinical signs and/or symptoms. These include recurrent chest pain, cardiac arrhythmias, cardiogenic shock, and mechanical complications of MI.

Recurrent chest pain may be due to ischemia in the territory of the original infarction, pericarditis, myocardial rupture, or pulmonary embolism.

Recurrent angina is experienced by 20% to 30% of patients after MI who receive fibrinolytic therapy and up to 10% of patients in the early time period following percutaneous revascularization. These symptoms may represent recurrence of ischemia or infarct extension.

Assessment of the patient may include evaluation for new murmurs or friction rubs, ECG to assess for new ischemic changes, cardiac enzymes (troponin and CK-MB), echocardiography, and repeat coronary angiography if indicated.

Patients with recurrent chest pain should continue to receive ASA, clopidogrel, heparin, nitroglycerin, and β-adrenergic antagonist therapy.

If recurrent angina is refractory to medical treatment, repeat coronary angiography and intervention should be considered along with possible placement of an IABP.

Acute pericarditis occurs 24 to 96 hours after MI in approximately 10% to 15% of patients. The associated chest pain is often pleuritic and may be relieved in the upright position. A friction rub may be noted on clinical examination and the ECG may show diffuse ST-segment elevation. Treatment is directed at pain management.

Aspirin is generally considered a first-line agent. NSAIDs such as indomethacin (25 to 50 mg qid) may be used if aspirin is not effective.

Glucocorticoids (prednisone, 1 mg/kg daily) may be useful if symptoms are severe and refractory to initial therapy. Steroid use should be deferred until at least 4 weeks after acute MI due to their adverse impact on infarct healing and risk of ventricular rupture (Am Heart J 1981;101:750). Colchicine may be beneficial for recurrent symptoms.

Heparin should be avoided in the setting of pericarditis with or without effusion as it may lead to pericardial hemorrhage.

Dressler syndrome is thought to be an autoimmune process characterized by malaise, fever, pericardial pain, leukocytosis, elevated sedimentation rate, and often

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a pericardial effusion. In contrast to acute pericarditis, Dressler syndrome occurs 1 to 8 weeks after MI. Treatment is identical to acute pericarditis.

Arrhythmias. Cardiac rhythm abnormalities are common following MI and may include conduction block, atrial arrhythmias, and ventricular arrhythmias. Arrhythmias that result in hemodynamic compromise require prompt, aggressive intervention. If the arrhythmia precipitates refractory angina or HF, urgent therapy is warranted. For all rhythm disturbances exacerbating conditions should be addressed, including electrolyte imbalances, hypoxia, acidosis, and adverse drug effects. (Details on specific arrhythmias can be found in Table 36.)

Transcutaneous and transvenous pacing. Conduction system disease that progresses to complete heart block or results in symptomatic bradycardia can be effectively treated with cardiac pacing. A transcutaneous pacing device can be used under emergent circumstances, and a temporary transvenous system can be used for longer-duration therapy.

Absolute indications for temporary transvenous pacing include asystole, symptomatic bradycardia, recurrent sinus pauses, complete heart block, and incessant VT.

Temporary transvenous pacing may also be warranted for new trifascicular block, new Mobitz II block, and for patients with LBBB who require a pulmonary artery catheter, given the risk of developing complete heart block.

Implantable cardioverter-defibrillators (ICDs) should not routinely be implanted in patients with reduced LV function following MI or those with ventricular tachycardia/fibrillation (VT/VF) in the setting of ischemia or immediately following reperfusion.

Routine insertion of ICDs into patients with reduced LV function immediately following MI does not improve outcomes (NEJM 2004;351:2481).

In contrast, patients who continue to have depressed LV function (EF <35%) greater than 1 month following MI benefit from ICD therapy (NEJM 2005;352: 225).

ICD therapy is also indicated for patients with recurrent episodes of sustained VT or VF despite coronary reperfusion.

Cardiogenic shock is an infrequent but serious complication of MI and is defined as hypotension in the setting of inadequate ventricular function to meet the metabolic needs of the peripheral tissue. Risk factors include prior MI, older age, diabetes, and anterior infarction. Organ hypoperfusion may manifest as progressive renal failure, dyspnea, diaphoresis, or mental status changes. Hemodynamic monitoring reveals elevated filling pressures (wedge pressure >20 mm Hg) and depressed cardiac index (<2.5 L/kg/min).

Patients with cardiogenic shock in the setting of MI have a mortality in excess of 50%. Such patients may require invasive hemodynamic monitoring and advanced therapeutic modalities including inotropic and mechanical support (Fig. 8).

Dobutamine is the inotrope of choice for patients with relatively preserved SBP (>90 mm Hg) as it both increases myocardial contractility and decreases ventricular afterload.

Dopamine is the preferred therapeutic agent in patients with an SBP less than 80 mm Hg. Addition of norepinephrine or phenylephrine may be required in markedly hypotensive patients (SBP <70 mm Hg).

Milrinone should be added in patients who are either not responding to dobutamine or who are experiencing excessive tachycardia in response to dobutamine. It should not be routinely used in patients with renal insufficiency.

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Patients in whom contraindications do not exist should be considered for insertion of an IABP, as inotropes increase myocardial oxygen consumption and may worsen ischemia (Table 37).

All patients with cardiogenic shock should undergo echocardiography to evaluate for mechanical complications of MI (see below).

For patients who present with cardiogenic shock, an early revascularization strategy is superior to initial medical stabilization. This benefit did not extend to patients older than 75 years (NEJM 1999;341:625).

Select patients with refractory HF who fail to respond to inotropes and require prolonged mechanical support may be considered for either cardiac transplant or placement of a LV assist device (LVAD).

Patients with large anterior infarcts, documented LV thrombus, or chronic atrial fibrillation should receive continued anticoagulant therapy. Heparin (UFH or LMWH) can be used until a therapeutic INR of 2 to 3 is achieved.

Patients with anterior apical akinesis or documented LV thrombus as assessed by echocardiography at the time of discharge should receive Coumadin for 3 to 6 months unless other indications warrant its continued use. The dose of aspirin should be reduced to 81 mg to decrease bleeding risk.

If HIT develops, heparin should be discontinued immediately and anticoagulation performed with a direct thrombin inhibitor (bivalirudin or argatroban).

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Mechanical complications

Aneurysm. After MI, the affected area of the myocardium may undergo infarct expansion and thinning, forming an aneurysm. The wall motion may become dyskinetic, and the endocardial surface is at risk for mural thrombus formation.

LV aneurysm is suggested by persistent ST elevation on the ECG and may be diagnosed by imaging studies including ventriculography, echocardiography, and MRI.

Anticoagulation is warranted to lower the risk of embolic events, especially if a mural thrombus is present (see above).

Surgical intervention may be appropriate if the aneurysm results in HF or ventricular arrhythmias that are not satisfactorily managed with medical therapy.

Ventricular pseudoaneurysm. Incomplete rupture of the myocardial free wall can result in formation of a ventricular pseudoaneurysm. In this case, blood escapes through the myocardial wall and is contained within the visceral pericardium. In the post-CABG patient, hemorrhage from frank ventricular rupture may be contained within the fibrotic pericardial space producing a pseudoaneurysm.

Echocardiography (TTE with contrast or TEE) is the preferred diagnostic test to assess for a pseudoaneurysm, often allowing differentiation from a true aneurysm.

Prompt surgical intervention for pseudoaneurysms is advised because of the high incidence of myocardial rupture.

Free wall rupture represents a catastrophic complication of acute MI accounting for 10% of early deaths. Rupture typically occurs within the first week after MI and presents with sudden hemodynamic collapse. This complication can occur after anterior or inferior MI but is more commonly seen in hypertensive women with a first-large transmural MI, treated late with fibrinolytic therapy, and given NSAIDs or glucocorticoids.

Echocardiography may identify patients with particularly thinned ventricular walls at risk for rupture.

Pericardiocentesis and intra-aortic balloon pump support may be necessary for patients awaiting emergent surgical correction.

Despite optimal intervention, mortality of free wall rupture remains greater than 90%.

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Papillary muscle rupture is a rare complication after MI and is associated with abrupt clinical deterioration. The posterior medial papillary muscle is most commonly affected due to its isolated vascular supply, but anterolateral and right ventricular papillary rupture have been reported. Of note, papillary muscle rupture may be seen in the setting of a relatively small MI.

The diagnostic test of choice is echocardiography with Doppler imaging as physical exam reveals a murmur in only ~50% of cases.

Initial medical therapy should include aggressive afterload reduction. Patients with refractory HF and those with hemodynamic instability may require inotropic support with dobutamine and/or intra-aortic balloon counterpulsation. Surgical repair is indicated in the majority of patients.

Ventricular septal rupture (or defect) formation is most commonly associated with anterior MI. The perforation may follow a direct course between the ventricles or a serpiginous route through the septal wall.

Diagnosis can be made by echocardiography with Doppler imaging and often requires TEE.

Diagnosis should be suspected in the postinfarct patient who develops HF symptoms and a new holosystolic murmur.

Stabilization with afterload reduction, inotropic support, and/or intra-aortic balloon pump may be necessary for hemodynamically unstable patients until definitive therapy with surgical repair can be performed.

In hemodynamically stable patients, surgery is best deferred for at least a week to improve patient outcome. Left untreated, mortality approaches 90%.

Percutaneous device closure in the cardiac catheterization laboratory can be performed on a compassionate basis in select patients with an unacceptable surgical risk.

Table 36 Arrhythmias Complicating MI

Arrhythmia

Treatment

Comments

Intraventricular conduction delays

None

The left anterior fascicle is most commonly affected because of isolated coronary blood supply.

Bifascicular and trifascicular block may progress to complete heart block and other rhythm disturbances.

Sinus bradycardia

None

Sinus bradycardia is common in patients with RCA infarcts.

Atropine 0.5 mg

Temporary pacinga

In the absence of hypotension or significant ventricular ectopy, observation is indicated.

AV block

Temporary pacinga

First-degree AV block usually does not require specific treatment.

Mobitz I second-degree block occurs more often with inferior MI. The block is usually within the His bundle and does not require treatment unless symptomatic bradycardia is present.

Mobitz II second-degree AV block originates below the His bundle and is more commonly associated with anterior MI. Because of the significant risk of progression to complete heart block, patients should be observed in the CCU and treated with temporary pacing if symptomatic.

Third-degree AV block complicates large anterior and RV infarcts. In patients with anterior MI, third-degree heart block often occurs 12-24 hr after initial presentation and may appear suddenly. Temporary pacing is recommended because of the risk of progression to ventricular asystole.

Sinus tachycardia

Noneb

Sinus tachycardia is common in patients with acute MI and is often due to enhanced sympathetic activity resulting from pain, anxiety, hypovolemia, anxiety, heart failure, or fever.

Persistent sinus tachycardia suggests poor underlying ventricular function and is associated with excess mortality.

Atrial fibrillation and flutter

β-Blockers

Atrial fibrillation and flutter are observed in up to 20% of patients with acute MI.

Anticoagulation

Cardioversion

Because atrial fibrillation and atrial flutter are usually transient in the acute MI period, long-term anticoagulation is often not necessary after documentation of stable sinus rhythm.

Accelerated junctional rhythm

None

Accelerated junctional rhythm occurs in conjunction with inferior MI. The rhythm is usually benign and warrants treatment only if hypotension is present. Digitalis intoxication should be considered in patients with accelerated junctional rhythm.

Ventricular premature depolarizations (VPDs)

β-Blockers if symptomaticc

VPDs are common in the course of an acute MI.

Prophylactic treatment with lidocaine or other antiarrhythmics has been associated with increased overall mortality and is not recommended (NEJM 1989; 321:406).

Accelerated idioventricular rhythm (AIVR)

None

Commonly seen within 48 hr of successful reperfusion and is not associated with an increased incidence of adverse outcomes.

If hemodynamically unstable, sinus activity may be restored with atropine or temporary atrial pacing.

Ventricular tachycardia (VT)

Cardioversion for sustained VT

Nonsustained ventricular tachycardia (NSVT, <30 sec) is common in the first 24 hr after MI and is only associated with increased mortality when occurring late in the post-MI course.

Lidocaine or amiodarone for 24-48 hrd

Sustained VT (>30 sec) during the first 48 hr after acute MI is associated with increased in-hospital mortality.

Ventricular fibrillation (VF)

Unsynchronized cardioversion

VF occurs in up to 5% of patients in the early post-MI period and is life threatening.

Lidocaine or amiodarone for 24-48 hrd

a Atropine and temporary pacing should only be used for symptomatic or hemodynamically unstable patients.

b The use of β-blockers in the setting of sinus tachycardia and poor LV function may result in decompensated heart failure.

c β-Blockers should be used with caution in the setting of bradycardia and frequent VPDs as they may increase the risk of polymorphic VT.

d Lidocaine should be used as a 1 mg/kg bolus followed by a 1 to 2 mg/kg/hr infusion. Amiodarone should be given as a 150 to 300 mg bolus followed by an infusion of 1 mg/kg/hr for 6 hours and then 0.5 mg/kg/hr for 18 hours.

Figure 8. Recommended diagnostic and therapeutic strategy for patients presenting with STEMI and cardiogenic shock. 1PCI may be preferable if CABG cannot be readily performed or if surgery imposes unacceptable risk. 2Advanced heart therapy modalities including percutaneous LV assist devices (TandemHeart, Impella), external ventricular assist devices, and extracorporeal membrane oxygenation (ECMO) may be required prior to placement of a permanent LVAD or cardiac transplant. PCI, percutaneous coronary intervention; WMA, wall motion abnormality; TEE, transesophageal echocardiography; IABP, intra-aortic balloon counterpulsation; LVAD, left ventricular assist device; CABG, coronary artery bypass graft.

Table 37 Intra-Aortic Balloon Counterpulsation

Indications

Contraindications

Monitoring

Cardiogenic shock, pump failure

Papillary muscle rupture

Severe ischemic mitral regurgitation

VSD

Facilitation of unprotected left main and LAD angioplasty or CABG

Complex PCI with severe underlying CAD

Aortic insufficiency

Severe peripheral vascular disease

Systemic infection, sepsis

Daily chest x-ray, platelet count, and creatinine

Regular evaluation of lower extremity pulses

Heparin infusion (PTT)

VSD, ventricular septal defect; LAD, left anterior descending artery; CABG, coronary artery bypass graft; PCI, percutaneous coronary intervention.

MONITORING/FOLLOW-UP

Routine office visits 1 month after discharge and every 3 to 12 months thereafter are suggested for the patient presenting with an acute MI.

Patients should be instructed to seek more frequent or urgent follow-up evaluation if they experience any noticeable change in their clinical status.

Specific plans for long-term follow-up care should be individualized based upon clinical status, anatomy, prior interventions, and change in symptoms.

A stress imaging study is appropriate for patients who have a significant change in clinical status (either HF or angina). Routine testing is not warranted in patients without change in clinical status or in those with an estimated annual mortality (by prior risk assessment) of <1%.

Coronary angiography should be considered for patients with significant ischemic burden on stress testing that is potentially amenable to revascularization or those with marked limitations of ordinary activity despite maximal medical therapy.