Sublingual

Sympathetic nervous system Shortness of breaih Stroke volume System ic vascular resistance L umor necrosis factor-« Vasopressin type la Vasopressin type 2 Ventricular assist device

^ Self-assessment questions and answers are available at ht-tp://www. mhpharmacotherapy. com/pp.html.

REFERENCES

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9. Mann DL. Inflammatory mediators and the failing heart—Past, present, and the foreseeable future. Circ Res 2002;91:988-998.

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12. Consensus recommendations for the management of chronic heart failure. On behalf of the membership of the advisory council to improve outcomes nationwide in heart failure. Am J Cardiol 1999;83(2A):1A-38A.

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17. De Bruyne LK. Mechanisms and management of diuretic resistance in congestive heart failure. Postgrad Med J 2003;79:268-271.

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21. Pfeffer MA, Braunwald E, Move LA, et al. Effect of Captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the survival and ventricular enlargement trial. N Engl J Med 1992;327:669-677.

22. Packer M, Wilson-Poole PA, Armstrong PW, et al. Comparative effects of low-and high doses of the angiotensin-converting enzyme inhibitor, lisinopril, or morbidity and mortality in chronic heart failure. Circulation 1999;100:2312-2318.

23. Pitt B, Poole-Wilson PA, Segal R, et al., for the ELITE II Investigators. Effect of losartan compared with captopril on mortality in patients with symptomatic heart failure: Randomised trial—The Losartan Heart Failure Survival Study ELITE II. Lancet 2000;355:1582-1587.

24. Cohn JN, Tognoni G, for the Valsartan Heart Failure Trial Investigators. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med 2001;345:1667-1675.

25. Pfeffer MA, Swedberg K, Granger CB, et al., for the CHARM Investigators and Committees. Effects of candesartan on mortality and morbidity in patients with chronic heart failure: The CHARM-Overall programme. Lancet 2003;362:759-766.

26. Cohn JN, Archibald DG, Ziesche S, et al. Effect of vasodilator therapy on mortality in chronic congestive heart failure. N Engl J Med 1986;314:1547-1552.

27. Cohn JN, Johnson G, Ziesche S, et al. A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure. N Engl J Med 1991;325:303-310.

28. Taylor AL, Ziesche S, Yancy C, et al. Combination of isosorbide dinitrate and hydralazine in blacks with heart failure. N Engl J Med 2004;351(20):2049-2057.

29. Packer M, Bristow MR, Cohn JN, et al., for the U.S. Carvedilol Heart Failure Study Group. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. N Engl J Med 1996;334: 1349-1355.

30. CIBIS-II Investigators and Committees. The cardiac insufficiency bisoprolol study II (CIBIS-II): A randomized trial. Lancet. 1999;353: 9-13.

31. MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL randomized intervention trial in congestive heart failure (MERIT-HF). Lancet 1999;353:2001-2007.

32. Packer M, Coats AJ, Fowler MB, et al., for the Carvedilol Prospective Randomized Cumulative Survival Study Group. N Engl J Med 2001;344(22):1651-1658.

33. Poole-Wilson PA, Swedberg K, Cleland JG, et al., for the COMET Investigators. Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the Carvedilol or Metoprolol European Trial (COMET): Randomized controlled trial. Lancet 2003;362:7-13.

34. Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med 1999;341(10):709-717.

35. Pitt B, Williams G, Remme W, et al. Eplerenone, a selective aldosterone antagonist, in patients with left ventricular dysfunction after myocardial infarction (EPHESUS). N Engl J Med 2003;348(14):1309-1321.

36. The Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients with heart failure. The Digitalis Investigation Group. N Engl J Med 1997;336:525-533.

37. Adams KF, Gheorghiade M, Uretsky BF, et al. Clinical benefits of low serum digoxin concentrations in heart failure. J Am Coll Cardiol 2002;39:946-953.

38. Rathore SS, Curtis JP, Wang Yongfei, et al. Association of serum digoxin concentration and outcomes in patients with heart failure. JAMA 2003;289:871-878.

39. Packer M, O'Connor CH, Ghali JK, et al. Effect of amlodipine on morbidity and mortality in severe chronic heart failure. N Engl J Med 1996;335:1107-1114.

40. Cohn JN, Ziesche S, Smith R, et al. Effect of the calcium antagonist felodipine as supplementary vasodilator therapy in patients with chronic heart failure treated with enalapril. Circulation 1997;96:856-863.

41. Lip GY, Gibbs CR. Antiplatelet agents versus control or anticoagulation for heart failure in sinus rhythm: A Cochrane systematic review. Q J Med 2002;95:461-468.

42. Fuster V, Ryde'n LE, Asinger RW, et al., for the Committee to Develop Guidelines for the Management of Patients with Atrial Fibrillation. ACC/AHA/ESC guidelines for the management of patients with atrial fibrillation: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines and Policy Conferences. (Committee to Develop Guidelines for the Management of Patients With Atrial Fibrillation). J Am Coll Cardiol 2001;38:1231-1266.

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Aurigenuna GP, Gaasch WH. Diastolic heart failure. N Engl J Med 2004;351(11):1097-1105.

Pearson GD, Veille JC, Rahimtoola S, et al. Peripartum cardiomyopathy: National Heart, Lung, and Blood Institute and Office of Rare Diseases (National Institutes of Health) workshop recommendations and review. JAMA 2000;283(9):1183-1188.

Tidswell M. Peripartum cardiomyopathy. Crit Care Clin 2004;20:777-788.

Stevenson LW. Tailored therapy to hemodynamic goals for advanced heart failure. Eur J Heart Fail 1999(Aug);[email protected]):251-257.

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7 Ischemic Heart Disease

Larisa H. Cavallari and Robert J. DiDomenico

LEARNING OBJECTIVES

Upon completion of the chapter, the reader will be able to:

1. Identify risk factors for the development of ischemic heart disease (IHD).

2. Differentiate between the pathophysiology of chronic stable angina and acute coronary syndromes (ACSs).

3. Recognize the symptoms and diagnostic criteria of IHD in a specific patient.

4. Identify the treatment goals of IHD and appropriate lifestyle modifications and pharmacologic therapy to address each goal.

5. Design an appropriate therapeutic regimen for the management of IHD based on patient-specific information.

6. Formulate a monitoring plan to assess effectiveness and adverse effects of an IHD drug regimen.

KEY CONCEPTS

© Ischemic heart disease (IHD) results from an imbalance between myocardial oxygen demand and oxygen supply that is most often due to coronary atherosclerosis. Common clinical manifestations of IHD include chronic stable angina and the acute coronary syndromes (ACSs) of unstable angina, non-ST-segment elevation myocardial infarction (MI), and ST-segment elevation MI.

Early detection and aggressive modification of risk factors is one of the primary strategies for delaying IHD progression and preventing IHD-related events including death.

Patients with chest pressure or heaviness that is provoked by activity and relieved with rest should be assessed for IHD. Sharp pain is not a typical symptom of IHD. Some patients may experience discomfort in the neck, jaw, shoulder, or arm rather than, or in addition to, the chest. Pain may be accompanied by nausea, vomiting, or diaphoresis.

'O' The major goals for the treatment of IHD are to prevent ACSs and death, alleviate acute symptoms of myocardial ischemia, prevent recurrent symptoms of myocar-dial ischemia, and avoid or minimize adverse treatment effects.

O Both 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) and angiotensin-converting enzyme (ACE) inhibitors are believed to provide vasculo-protective effects, and in addition to antiplatelet agents, have been shown to reduce the risk of acute coronary events and death in patients with IHD. Angiotensin receptor blockers (ARBs) may be used in patients who cannot tolerate ACE inhibitors because of side effects (e.g., chronic cough). P-Blockers have been shown to decrease morbidity and improve survival in patients who have suffered a MI.

Antiplatelet therapy with aspirin should be considered for all patients without contraindications, particularly in patients with a history of MI. Clopidogrel may be considered in patients with allergies or intolerance to aspirin. In some patients, combination antiplatelet therapy with aspirin and clopidogrel may be used.

To control risk factors and prevent major adverse cardiac events, statin therapy should be considered in all patients with IHD, particularly in those with elevated low-density lipoprotein cholesterol. In the absence of contraindications, ACE inhibitors should be considered in IHD patients who also have diabetes mellitus, left ventricular dysfunction, history of MI, or any combination of these. Angiotensin receptor blockers maybe used in patients who cannot tolerate ACE inhibitors because of side effects.

® All patients with a history of angina should have sublingual nitroglycerin tablets or spray to relieve acute ischemic symptoms. Patients should be instructed to use one dose (tablet or spray) every 5 minutes until pain is relieved and to call 911 if pain is unimproved or worsens 5 minutes after the first dose.

P-Blockers are first-line therapy for preventing ischemic symptoms, particularly in patients with a history of Ml Long-acting calcium channel blockers and long-acting nitrates maybe added for refractory symptoms or substituted if a P-blocker is not tolerated.

® Patients should be monitored to assess for drug effectiveness, adverse drug reactions, and potential drug-drug interactions. Patients should be assessed for adherence to their pharmacotherapeutic regimens and lifestyle modifications.

INTRODUCTION

Ischemic heart disease (IHD) is also called coronary heart disease (CHD) or coronary artery disease. The term "ischemic" refers to a decreased supply of oxygenated blood, in this case to the heart muscle. IHD is caused by the narrowing of one or more of the major coronary arteries that supply blood to the heart, most commonly by atherosclerotic plaques. Atherosclerotic plaques may impede coronary blood flow to the extent that cardiac tissue distal to the site of the coronary artery narrowing is deprived of sufficient oxygen in the face of increased oxygen demand. IHD results from an imbalance between myocardial oxygen supply and oxygen demand (Fig. 7—1). Common clinical manifestations of IHD include chronic stable angina and the acute coronary syndromes (ACSs) of unstable angina, non-ST-segment elevation myocardial infarction (MI), and ST-segment elevation MI.

Angina pectoris, or simply angina, is the most common symptom of IHD. Angina is discomfort in the chest that occurs when the blood supply to the myocardium is compromised. Chronic stable angina is defined as a chronic and predictable occurrence of chest discomfort due to transient myocardial ischemia with physical exertion or other conditions that increase oxygen demand. The primary focus of this chapter is on the management of chronic stable angina. However, some information is also provided related to ACS, given the overlap between the two disease states. The American College of Cardiology and the American Heart Association have jointly published practice guidelines for the management of patients with chronic stable angina,

and the reader is referred to these guidelines for further information. '

EPIDEMIOLOGY AND ETIOLOGY

IHD affects over 16 million Americans and is the leading cause of death for both men and women in the United States.3 The incidence of IHD is higher in middle-aged men compared to women. However, the rate of IHD increases two-to threefold in women after menopause. Chronic stable angina is the initial manifestation of IHD in about 50% of patients, whereas unstable angina or MI is the first sign of IHD in other patients. Chronic stable angina is associated with considerable patient morbidity, with many affected patients eventually requiring hospitalization for ACS. In ad dition, chronic stable angina has a major negative impact on health-related quality of life. Thus, in patients with chronic stable angina, it is important to optimize pharmacotherapy to reduce symptoms, improve quality of life, slow disease progression, and prevent ACS.

FIGURE 7-1. This illustration depicts the balance between myocardial oxygen supply and demand and the various factors that affect each. It should be noted that diastolic filling time is not an independent predictor of myocardial oxygen supply per se, but rather a determinant of coronary blood flow. On the left is myocardial oxygen supply and demand under normal circumstances. On the right is the mismatch between oxygen supply and demand in patients with IHD. In patients without IHD, coronary blood flow increases in response to increases in myocardial oxygen demand. However, in patients with IHD, coronary blood flow cannot sufficiently increase (and may decrease) in response to increased oxygen demand resulting in angina. (IHD, ischemic heart disease; Po2, partial pressure of oxygen.)

FIGURE 7-1. This illustration depicts the balance between myocardial oxygen supply and demand and the various factors that affect each. It should be noted that diastolic filling time is not an independent predictor of myocardial oxygen supply per se, but rather a determinant of coronary blood flow. On the left is myocardial oxygen supply and demand under normal circumstances. On the right is the mismatch between oxygen supply and demand in patients with IHD. In patients without IHD, coronary blood flow increases in response to increases in myocardial oxygen demand. However, in patients with IHD, coronary blood flow cannot sufficiently increase (and may decrease) in response to increased oxygen demand resulting in angina. (IHD, ischemic heart disease; Po2, partial pressure of oxygen.)

Conditions Associated With Angina

Figure 7-2 shows the anatomy of the coronary arteries. The major epicardial coronary arteries are the left main, left anterior descending, left circumflex, and right coronary arteries. Atherosclerosis involving one or more of the major coronary arteries or their principal branches is the major cause of angina. Vasospasm at the site of an atherosclerotic plaque may contribute to angina by further restricting blood supply to the distal myocardium. Less commonly, vasospasm in coronary arteries with no or minimal atherosclerotic disease can produce angina and even precipitate ACS. This type of vasospasm is referred to as variant or Prinzmetal angina. Other nonatherosclerotic conditions that can cause angina-like symptoms are listed in Table 7-1. It is important to differentiate the etiology of chest discomfort since treatment varies depending on the underlying disease process.

Proximal right

Dipiro Pharmacotherapy Table Emesis

diagonal

Distal right diagonal

First septal anterior descending First obtuse marginal Second oMuse marginal Third obtuse marginal

Proximal right

Left main

Proximal circumflex diagonal

Acute marginal

Mid left anterior descending

Distal right diagonal

First septal

Distal left anterior descending

Sternocostal aspect

Inferior septal

Lett

Right posterior lateral segment

Inferior septal

FIGURE 7-2. Coronary artery anatomy with sternocostal and diaphragmatic views. (Reproduced from Talbert RL Ischemic heart disease. In: DiPiro JT, Talbert RL, Yee GC, et al. (eds.) Pharmacotherapy: A Pathophysiologic Approach. 6th ed. New York: McGraw-Hill; 2005: 263, with permission.)

Risk Factors

Factors that predispose an individual to IHD are listed in Table 7-2. Hypertension, diabetes, dyslipidemia, and cigarette smoking are associated with endothelial dysfunction and potentiate atherosclerosis of the coronary arteries. The risk for IHD increases twofold for every 20 mm Hg increment in systolic blood pressure and up to eightfold in the presence of diabetes.4,5 Physical inactivity and obesity independently increase the risk for IHD, in addition to predisposing individuals to other cardiovascular risk factors, namely hypertension, dyslipidemia, and diabetes.

Table 7-1 Nonatherosclerotic Conditions That Can Cause Angina-Like Symptoms

Organ System_Condition_

Ca rdiac Aor tic dissection, coronary artery vasospasm, pericarditis, valvular heart diseaser severe uncontrolled hypertension

Noncardiac Anemia, anxiety disorders, carbon monoxide poisoning, cocaine user esophageal reflux, peptic ulcerr pleuritic pneumonia, pneumothorax, pulmonary emboiusr pulmonary hypertension, thyrotoxicosis

Table 7-2 Major Risk Factors for Ischemic Heart Disease

Modifiable

Nonmodifjable

Cigarette smoking

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