Silent Myocardial Ischemia: Diagnosis, Treatment, and Prognosis

February 2, 2009
Tera D. Moore, PharmD

Silent myocardial ischemia (SMI)- objective documented ischemia in the absence of chest discomfort or other anginal equivalents-is a major component of the total ischemic burden for patients with ischemic heart disease.1 In the United States, an estimated 2 to 3 million persons with stable coronary artery disease (CAD) have evidence of silent ischemia. 2

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Clinical Significance of Silent Myocardial Ischemia

Silent myocardial ischemia (SMI)- objective documented ischemia in the absence of chest discomfort or other anginal equivalents-is a major component of the total ischemic burden for patients with ischemic heart disease.1 In the United States, an estimated 2 to 3 million persons with stable coronary artery disease (CAD) have evidence of silent ischemia. 2 About 40% of patients with ischemic heart disease have acute episodes of myocardial ischemia during their lifetime; 75% of these episodes cause no symptoms and are considered “silent.”1

Greater awareness of the incidence of silent ischemia in high-risk populations (eg, persons with diabetes) can help reduce cardiovascular events and death rates. In this review, we outline the evidence that supports the relationship between SMI and the risk of future cardiovascular events. We also offer recommendations for the diagnosis and management of SMI.

COHN CLASSIFICATION OF SILENT ISCHEMIA

Patients at increased risk for cardiovascular events include those with stable angina, unstable angina, postinfarction angina, or variant angina; those who have survived cardiac arrest or have had a heart transplant or percutaneous coronary intervention or bypass surgery; and those who have diabetes (Figure) or multiple coronary risk factors.3

According to the Cohn classification, 4 patients with silent ischemia are stratified into types I, II, or III:
Type I silent ischemia is the least common form. It occurs in asymptomatic patients with obstructive CAD who do not experience anginal symptoms at any time.
Type II silent ischemia most commonly occurs in patients with a documented previous myocardial infarction (MI).
Type III is the most common form; it occurs in patients with chronic stable angina, unstable angina, or variant angina.

PROGNOSTIC SIGNIFICANCE OF SILENT MYOCARDIAL ISCHEMIA

In patients with ischemic heart disease, SMI occurs more often than does the typical episode of angina. A large body of evidence shows that cardiovascular outcomes for patients with SMI are similar to those with symptomatic ischemia.5,6

SMI and cardiovascular risk. Weiner and colleagues5 evaluated a cohort of patients with CAD to determine whether SMI that occurred during exercise increased the risk of MI or sudden death. Of 880 patients who, within 1 month of undergoing catheterization, had a symptom-limited maximal exercise test using Bruce protocol, 424 evidenced ST-segment depression of 1 mm or more without angina. The investigators compared this group with 456 CAD patients who had ST-segment depression and angina during exercise testing, and with 1019 controls without CAD.

The percentages of CAD patients who experience subsequent MI or sudden death were similar in the silent ischemia and angina groups (20% and 9% vs 18% and 7%, respectively). However, the likelihood of MI or sudden death in patients with silent ischemia increased with the severity of CAD and left ventricular (LV) dysfunction. Of patients presenting with SMI, 62% had 3-vessel CAD with abnormal LV function and experienced subsequent MI or sudden death, compared with only 10% of patients with 1-vessel CAD and preserved LV function. The adverse event rate for patients with 3-vessel CAD and SMI was greater than that for patients with 3-vessel disease and angina. Of note, 48% of patients in the cohort had SMI during exercise testing; 65% had a history of angina at the baseline evaluation. Clinically, patients without warning signs of angina would be at increased risk.

Recently, Erne and colleagues,7 in the Swiss Interventional Study on Silent Ischaemia type I (SWISSI I) randomized multicenter trial, enrolled 263 asymptomatic patients with 1 CAD risk factor, with silent ischemia identified by exercise treadmill testing (ETT) stress imaging. Fifty-one patients were randomized to antianginal drug treatment. Over the next 11 years, 3 patients in the medical treatment group experienced cardiac death, nonfatal MI, or acute coronary syndrome compared with 17 in the control group (P < .001).

SMI and chronic stable angina. Deedwania and Carbajal8 studied a small cohort of patients with documented CAD and chronic stable angina who underwent 24-hour ambulatory ECG monitoring while receiving antianginal medications prescribed by their primary care physicians. Forty-six patients (43%) had evidence of SMI during monitoring; 61 patients (57%) had no evidence of ischemia. In the first group, most ischemic events were silent (87%) and comprised 84% of the total ischemia time. Cumulative survival at 1 year and 2 years was significantly less (P = .023) for patients with SMI during ambulatory ECG monitoring.

In a more recent trial (the Heart and Soul Study), Gehi and associates9 evaluated self-reported angina by questionnaire and inducible ischemia using treadmill stress echocardiography in 937 outpatients with chronic stable angina during a 3.9-year followup period. They found that more than 80% of these patients did not report angina, with a 2-fold increase in recurrent MI or coronary heart disease (CHD) death (adjusted hazard ratio, 2.1; 95% confidence interval, 1.3 - 3.5) (P = .005)

SMI and unstable angina. Gottlieb and colleagues10 studied patients with unstable angina whose symptomatic ischemia had been nearly eliminated with therapy. In this population, persistent SMI evident on Holter monitoring was associated with more severe CAD. Compared with patients in whom SMI was absent, those with SMI were more likely to experience early (within 30 days) adverse outcomes of MI or recurrent symptoms requiring revascularization, as well as late (after 2 years) adverse outcomes including death or recurrent MI. Similar observations were evident in patients after recent angioplasty.10,11

SMI following MI. Among patients about to be discharged following hospitalization for an MI, treadmill testing revealed that exerciseinduced ischemia with or without angina was associated with increased risk of coronary events and cardiac death.12,13 In addition, a prospective study by Narins and associates6 that evaluated 500 patients who underwent ambulatory monitoring and stress thallium scintigraphy 1 to 6 months after an episode of unstable angina or MI found that 75% of the patients had evidence of SMI.

SMI without documented CAD or angina. Two studies have detected a significant association between exercise testing-induced SMI and mortality. The Lipid Research Clinics Coronary Primary Prevention Trial enrolled 3806 asymptomatic men with hypercholesterolemia who were randomized to cholestyramine or placebo treatment groups; 8.2% had a positive ETT and over the next 7.4 years (mean) the mortality rate from CHD was 6.7% (21/315) in the positive ETT group and 1.3% (46/3460) in the negative ETT group.14

The Multiple Risk Factor Intervention Trial (MRFIT) enrolled 12,866 middle-aged men who were asymptomatic and had 2 or more cardiovascular risk factors.15 During the next 6 to 8 years of follow-up, patients in the special intervention programs to reduce blood pressure, lipid levels, and cigarette smoking had a 7% lower CAD mortality rate than the control population. Global risk reduction was beneficial in this population of patients with an abnormal ETT who had no previous documented CAD.

The SWISSI I evaluated asymptomatic subjects without CAD but with at least 1 risk factor for CAD who had silent ischemia on ETT confirmed by stress imaging.7 These patients were divided into an antianginal drug group (included aspirin) (n = 26) and a risk factor control group (n = 28). During the next 11 years of follow-up, 3 (12%) of the medical treatment group versus 17 (61%) of the risk factor control patients (P < .001) experienced cardiac death, nonfatal MI infarction, or acute coronary syndrome requiring hospitalization or revascularization. The investigators concluded that patients with positive ETT and documented abnormal stress imaging should receive aspirin and global risk reduction.

In another population-based study of 2682 men without CAD, exercise- induced ischemia increased mortality and the risk of acute coronary syndrome by 5.9- and 3-fold in patients who smoked, by 3.8- and 1.9- fold in patients with hypercholesterolemia, and by 4.7- and 2.2-fold in those with hypertension.16 These observations underscore the importance of determining absolute cardiovascular risk.

CLINICAL ASSESSMENT

Although this review focuses on SMI, a large percentage of patients with ischemic heart disease have both symptomatic and silent episodes. Symptomatic ischemia may not present with classic anginal symptoms but with anginal equivalents such as dyspnea, fatigue, or palpitations. Dyspnea is a subjective symptom with several possible causes; it is typically associated with heart failure or chronic lung disease. However, when dyspnea occurs in a patient who has cardiovascular risk factors, consider a cardiac cause.2

Additional symptoms may include palpitations (or a subjective description of “rapid heartbeat”) and fatigue Patients may describe fatigue as an inability to walk long distances or as feeling a sudden onset of weakness. Obtain a detailed history, including subjective changes as detailed above, and note any cardiovascular risk factors. Patients who exhibit these symptoms may need to be evaluated for CAD.

DIAGNOSTIC STUDIES

Several diagnostic tools can detect SMI. The most frequently used tests in clinical practice are ETT and ambulatory ECG, or Holter, monitoring. The Algorithm shows the patient populations for whom noninvasive testing for ischemic heart disease is recommended.

Exercise treadmill testing. This is the preferred tool to identify silent ischemia in patients with either symptomatic or asymptomatic disease. A diagnosis of CAD in asymptomatic patients, however, must be confirmed with radionuclide imaging (thallium perfusion scintigraphy or exercise ventriculography) because of the high rate of false-positive results with ETT.17,18 False-positive results are seen most often in patients with hypertension and are caused by ECG repolarization abnormalities that become evident during exercise in patients with LV hypertrophy. False-positive results are also commonly seen in women.

False-negative results on treadmill testing are particularly common among patients with diabetes and among those with physical disabilities that limit the extent to which they can exercise.19

No large randomized controlled trials have demonstrated a clinical benefit of ETT in this asymptomatic population. Because of insufficient evidence, the US Preventive Services Task Force (USPSTF), the American Heart Association, and the American College of Cardiology have recommended against using ETT as a screening tool.

However, the USPSTF and American Diabetes Association guidelines recognize the possible usefulness of ETT for patients with diabetes who are contemplating starting an exercise program, for persons with multiple CAD risk factors, for men older than 45 and women older than 55 years who plan to start a vigorous exercise program, and for those involved in high-risk occupations who are at risk for CAD.20 Furthermore, they found that ETT had no value in low-risk patients and recommended against routine screening in these patients.21

Ambulatory monitoring. This study is recommended to confirm or refute the presence of SMI in patients with a positive exercise test result.22 For initial diagnosis, however, reserve ambulatory monitoring for patients with ischemia following an acute coronary event and for patients with chronic stable angina who exhibit exerciseinducible ischemia.1 Unlike treadmill testing, ambulatory monitoring assesses ECG changes while patients engage in routine daily activities.

TREATMENT

Because SMI increases the risk of cardiovascular events, it is reasonable to use pharmacological therapy in an attempt to decrease the patient’s total ischemic burden.

β-Blockers. These seem to be the most effective agents; they reduce the incidence, frequency, duration, and severity of silent ischemia. 23-25 The Atenolol Silent Ischemia Study (ASIST) evaluated the effects of atenolol in asymptomatic or mildly symptomatic patients who had abnormal results on exercise thallium testing and silent ischemia documented by ambulatory ECG monitoring.26 Treatment with atenolol, 100 mg/d, reduced daily ischemia, as well as the risk of future adverse cardiac events at 1 year. Another effective treatment is to combine a longacting β-blocker with a long-acting nitrate.

Anti-ischemic efficacy can be evaluated by repeated Holter monitoring and titrating drug doses until the ischemic burden is suppressed by at least 50% or the maximum tolerated dose of a β-blocker is attained.

Calcium channel blockers. These agents, specifically amlodipine, long-acting nifedipine, and short- or long-acting diltiazem, have been shown to reduce ischemic episodes by 13% to 69%, and to decrease the duration of episodes by 6% to 68%. Combining a long-acting dihydropyridine calcium channel blocker (CCB) with a β-blocker has proved superior to either agent alone in reducing ischemia.27-29 If β-blocker therapy is not an option because of adverse effects or contraindications, consider combining a long-acting dihydropyridine CCB and a long-acting nitrate.

Revascularization. This is achieved with either percutaneous coronary interventions or coronary artery bypass grafting (CABG). Revascularization, regardless of the method, has not conclusively reduced the risk of MI or cardiovascular death in patients with chronic stable angina and preserved LV systolic function. Consider revascularization for patients with unacceptably frequent or severe angina that has not responded to optimized medical therapy, and for patients with such high-risk features as symptomatic multivessel disease, proximal left anterior descending or left main artery disease, LV systolic dysfunction, diabetes, a large area of myocardium at jeopardy on nuclear or echocardiographic stress testing, early onset of ischemia on stress testing, or STsegment depression of 2 mm or more.

Revascularization currently is not recommended for patients without anginal symptoms unless they meet the above criteria.30,31 Focus instead on steps to modify risk factors, such as blood pressure control, lipid lowering, smoking cessation, and lifestyle modifications including diet and exercise.

Comparison of treatment approaches. The Asymptomatic Cardiac Ischemia Pilot (ACIP) study evaluated the effects of 3 treatment strategies in patients with CAD who had no angina or who had symptoms that were well controlled with medical management but had at least 1 episode of SMI during 48-hour ambulatory ECG monitoring.32 The following approaches were compared in the study:
•Medications to suppress angina.
•Medications to suppress angina and ischemia as evidenced on ambulatory ECG.
•Revascularization with balloon angioplasty or CABG.

The 2 medication regimens were atenolol and nifedipine, and diltiazem and isosorbide dinitrate.

The primary end point of ACIP was suppression of ambulatory ECG ischemia at 12 weeks. After 1 year, revascularization proved superior to both medication cohorts. Mortality, MI, and nonprotocol revascularization or hospital admission at 1 year was 32%, 31%, and 18%, respectively, while the incidence of death was 4.4%, 1.6%, and 0%. At 2 years, mortality in the revascularization group was 1.1%, compared with 4.4% and 6.6% in the medication groups.33

References:

REFERENCES:


1

. Solomon H, DeBusk RF. Contemporary management of silent ischemia: the role of ambulatory monitoring.

Int J Cardiol.

2004;96:311-319.

2

. Stern S. Symptoms other than chest pain may be important in the diagnosis of “silent ischemia” or “the sounds of silence.”

Circulation.

2005;111:e435-e437.

3

. Conti CR. Silent cardiac ischemia.

Curr Opin Cardiol.

2002;17:537-542.

4

. Cohn PF. Should silent ischemia be treated in asymptomatic individuals?

Circulation.

1990;82 (3 suppl):II149-II154.

5

. Weiner DA, Ryan TJ, McCabe CH, et al. Risk of developing an acute myocardial infarction or sudden coronary death in patients with exercise-induced silent myocardial ischemia. A report from the Coronary Artery Surgery Study (CASS) registry.

Am J Cardiol.

1988;62:1155-1158.

6

. Narins CR, Zareba W, Moss AJ, et al. Clinical implications of silent versus symptomatic exerciseinduced myocardial ischemia in patients with stable coronary disease.

J Am Coll Cardiol.

1997;29:756-763.

7.

Erne P, Schoenenberger AW, Zuber M, et al. Effects of anti-ischaemic drug therapy in silent myocardial ischaemia type I: the Swiss Interventional Study on Silent Ischaemia type I (SWISSI I): a randomized, controlled pilot study.

Eur Heart J.

2007; 28:2110-2117.

8.

Deedwania PC, Carbajal EV. Silent ischemia during daily life is an independent predictor of mortality in stable angina.

Circulation.

1990;81:748-756.

9

. Gehi AK, Ali S, Na B, et al. Inducible ischemia and the risk of recurrent cardiovascular events in outpatients with stable coronary heart disease: the heart and soul study.

Arch Intern Med

. 2008;14: 1423-1428.

10

. Gottlieb SO, Weisfeldt ML, Ouwang P, et al. Silent ischemia predicts infarction and death during 2 year follow-up of unstable angina.

J Am Coll Cardiol.

1987;10:756-760.

11.

Nademanee K, Intarachot V, Josephson MA, et al. Prognostic significance of silent myocardial ischemia in patients with unstable angina.

J Am Coll Cardiol.

1987;10:1-9.

12

. Théroux P, Waters DD, Halphen C, et al. Prognostic value of exercise testing soon after myocardial infarction.

N Engl J Med.

1979;301:341-345.

13

. Gottlieb SH, Gerstenblith G, Achuff SC, et al. Ischemic ST segment changes by ambulatory Holter predict one-year mortality in high risk post-infarct patients.

Circulation.

1986;74:II-58.

14

. Ekelund LG, Suchindran CM, McMahon RP, et al. Coronary heart disease morbidity and mortality in hypercholesterolemic men predicted from an exercise test: the Lipid Research Clinics Coronary Primary Prevention Trial.

J Am Coll Cardiol.

1989; 14:556-563.

15

. Exercise electrocardiogram and coronary heart disease mortality in the Multiple Risk Factor Intervention Trial. Multiple Risk Factor Intervention Trial Research Group.

Am J Cardiol.

1985;55:16-24.

16

. Laukkanen JA, Kurl S, Lakka TA, et al. Exercise- induced silent myocardial ischemia and morbidity and mortality in middle-aged men.

J Am Coll Cardiol.

2001;38:72-79.

17

. Yeung AC, Vekshtein VI, Krantz DS, et al. The effect of atherosclerosis on the vasomotor response of coronary arteries to mental stress.

N Engl J Med.

1991;325:1551-1556.

18.

Deedwania PC. Should asymptomatic subjects with silent ischemia undergo further evaluation and follow-up?

Int J Cardiol.

1994;44:101-103.

19

. O’Rourke RA. Should patients with type 2 diabetes asymptomatic for coronary artery disease undergo testing for myocardial ischemia?

Nat Clin Pract Cardiovasc Med.

2005;2:492-493.

20

. American Diabetes Association.

Standards of medical care in diabetes-2007.

Diabetes Care. 2007; 30(suppl 1):S4-S41.

21

. Lauer M, Froelicher ES, Williams M, Kligfield P. Exercise testing in asymptomatic adults: a statement for professionals from the American Heart Association Council on Clinical Cardiology, Subcommittee on Exercise, Cardiac Rehabilitation, and Prevention.

Circulation.

2005;112:771-776.

22

. Deedwania PC. The need for a cost-effective strategy to detect ambulatory silent ischemia.

Am J Cardiol.

1994;74:1061-1062.

23

. Willich SN, Pohjola-Sintonen S, Bhatia SJ, et al. Suppression of silent ischemia by metoprolol without alteration of morning increase of platelet aggregability in patients with stable coronary artery disease.

Circulation.

1989;79:557-565.

24.

Cohn PF, Lawson WE. Effects of long-acting propranolol on AM and PM peaks in silent myocardial ischemia.

Am J Cardiol.

1989;63:872-873.

25

. Imperi G, Lambert CR, Coy K, et al. Effects of titrated beta blockade (metoprolol) on silent myocardial ischemia in ambulatory patients with coronary artery disease.

Am J Cardiol.

1987;60:519-524.

26

. Pepine CJ, Cohn PF, Deedwania PC, et al. Effects of treatment on outcome in mildly symptomatic patients with ischemia during daily life. The Atenolol Silent Ischemia Study (ASIST).

Circulation.

1994;90:762-768.

27

. Deanfield JE, Detry JM, Lichtlen PR, et al. Amlodipine reduces transient myocardial ischemia in patients with coronary artery disease: double-blind Circadian Anti-Ischemia Program in Europe (CAPE Trial).

J Am Coll Cardiol.

1994;24:1460-1467.

28.

Egstrup K. Randomized double-blind comparison of metoprolol, nifedipine, and their combination in chronic stable angina: effects on total ischemic activity and heart rate at onset of ischemia.

Am Heart J.

1988;116:971-978.

29

. Davies RF, Habibi H, Klinke WP, et al. Effect of amlodipine, atenolol and their combination on myocardial ischemia during treadmill exercise and ambulatory monitoring. Canadian Amlodipine/Atenolol in Silent Ischemia Study (CASIS) Investigators.

J Am Coll Cardiol.

1995;25:619-625.

30.

Gibbons RJ, Abrams J, Chatterjee K, et al. ACC/ AHA 2002 guideline update for the management of patients with chronic stable angina-summary article: a report of the American College of Cardiology/ American Heart Association Task Force on practice guidelines (Committee on the Management of Patients with Chronic Stable Angina).

J Am Coll Cardiol.

2003;41:159-168.

31

. Eagle KA, Guyton RA, Davidoff R, et al. ACC/ AHA 2004 guideline update for coronary artery bypass graft surgery: summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Update the 1999 Guidelines for Coronary Artery Bypass Graft Surgery). Circulation. 2004;110: 1168-1176.

32.

Rogers WJ, Bourassa MG, Andrews TC, et al. Asymptomatic Cardiac Ischemia Pilot (ACIP) Study: outcome at 1 year for patients with asymptomatic cardiac ischemia randomized to medical therapy or revascularization. The ACIP Investigators.

J Am Coll Cardiol.

1995;26:594-605.

33

. Davies RF, Goldberg AD, Forman S, et al. Asymptomatic Cardiac Ischemia Pilot (ACIP) study two-year follow-up: outcomes of patients randomized to initial strategies of medical therapy versus revascularization.

Circulation.

1997;95:2037-2043.

34

. Whiteley L, Padmanabhan S, Hole D, Isles C. Should diabetes be considered a coronary heart disease risk equivalent? Results from 25 years of follow- up in the Renfrew and Paisley survey.

Diabetes Care.

2005;28:1588-1593.

Therapeutic Agents in This Article


Amlodipine (Norvasc)
Aspirin
Atenolol (Tenormin)
Cholestyramine (Locholest, Questran)
Dilitizaem (Cardizem, Tiazac)
Isosorbide dinitrate (Imdur, Ismo, Isordil,
Monoket)
Nifedipine (Adalat, Procardia)