Noninvasive Assessment of Asymptomatic Individuals at Risk of Coronary Heart Disease.Part b 7

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6.5 Noncardiac (Vascular) Surgery . . . 147

6.5.1 Clinical . . . 147

6.5.2 Echocardiography . . . 147

6.5.3 Alternate Strategies for Screening . . . 148

6.5.4 Appropriate Responses . . . 148

7. Conclusion . . . 149

1. Background

Silent myocardial ischemia may occur at rest and on exertion^1,2and the prevalence of undiagnosed coronary artery disease (CAD) in asymptomatic 50 year olds has been estimated at 15%–20% in men and 5% in women.³ Although coronary angiography is the current gold standard in detection of CAD, American Heart Association (AHA)/American College of Cardiology guidelines recommend “that coronary angiography is indicated for patients found to have high-risk abnormalities on noninvasive testing and that noninvasive procedures for identifying patients with stress-induced ischemia, should remain the primary means of risk stratification.”⁴ This second part of Chapter 7 deals with the role of noninvasive imaging in assessing asymptomatic individuals and particularly specific higher-risk groups such as patients with diabetes mellitus, end-stage renal failure (ESRF), cardiac transplant, and those awaiting surgery for peripheral vascular disease. It complements the first part not only by the shift of the 1. Background . . . 137

2. Screening . . . 138

3. Statistical Considerations and the Clinical Detection of Risk . . . 138

4. Echocardiography as a Screening Tool . . . 139

4.1 Prognostic Value of Resting Echocardiography . . . 139

4.2 Stress Echo as Screening Tool . . . 139

5. Management Implications of Positive Stress Echocardiograms . . . 139

6. Use of Stress Echo in High-risk Patient Groups . . . 140

6.1 Multiple Risk Factors (Including Metabolic Syndrome/Obesity) . . . 140

6.1.1 Clinical . . . 140

6.2 Diabetes Mellitus . . . 142

6.2.1 Clinical . . . 142

6.3 End-stage Renal Failure . . . 143

6.3.1 Clinical . . . 143

6.4 Cardiac Transplants . . . 146

6.4.1 Clinical . . . 146

7

Noninvasive Assessment of Asymptomatic Individuals at Risk of Coronary Heart Disease. Part b

Dhrubo Rakhit and Thomas H. Marwick

137

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emphasis on speciﬁc groups but also by its focus on echocardiography. The latter is a versatile modality with very good diagnostic and prognostic value^5–7that does not use ionizing radia- tion and is therefore a very attractive option for assessing the patients discussed in this chapter.

2. Screening

The value of screening is to reduce morbidity and mortality from a disease. For screening to be effective, the disease should have an early asymptomatic stage and have important health consequences. A screening test should be cost effective, have a low false-positive and false-negative rate, be able to detect disease earlier than it would otherwise present and there must be an appropriate therapy to prevent the outcome that would have ensued.⁸ Specifically, screening in high-risk patients can only be justified if a) a suitable cost-effective approach to identify CAD is available, and b) a treatment strategy for positive cases identified by the screening procedure is feasible.

There are several social reasons why asymptomatic individuals request screening for CAD.

These include family history, presence of risk factors, anxiety, dangerous or important occupa- tion (e.g., airline pilots or executives). From a medical standpoint, the main rationale is the detection of asymptomatic CAD, which is thought to account for 20%–25% of cases of sudden death.⁹ It has been proposed that the

most effective primary prevention of sudden death may be prevention of coronary events.¹⁰

3. Statistical Considerations and the Clinical Detection of Risk

Bayes’ theory states that the probability of a disease being present after a positive or negative test depends on the pretest probability of the disease.¹¹Therefore, if the pretest probability of a disease is low, then even with a highly sensitive or speciﬁc test, the posttest probability will be low (see Figure 7b.1).

To maximize the chances of obtaining a positive test, a low-risk (“screening”) group should undergo some process whereby the patients at lowest risk are removed from the screening program. This process effectively enriches the testing group with individuals at higher risk.

Indeed, the use of stress echocardiography (SE) in a group of low-risk patients is not cost effective,¹²whereas in patients at higher risk it has been shown to provide incremental beneﬁt in risk evaluation.¹³

Various clinical approaches to allocating risk are available and include coronary prediction models, such as those based on Framingham data¹⁴for long-term outcome or Eagle’s criteria¹⁵ for perioperative outcome. Because stress- induced wall motion abnormalities may be man- ifested even before symptoms occur (Figure 7b.3) sE has been used to identify CAD in the high-

Figure 7b.1. Importance of pretest prob- ability.Even with the most sensitive possible test, testing of low-probability patients is associated with high numbers of false- positive results.

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4.2 Stress Echo as Screening Tool

SE is considered a useful, feasible, and safe technique for detecting the presence, localization, and extent of CAD.²⁵In comparison with myocardial perfusion imaging (MPI), SE is more speciﬁc but has a lower sensitivity for the detection of CAD^26,27– this may actually be of some beneﬁt in its application to a screening population. SE has been shown to be of prognostic and/or diagnostic value in patients with right bundle branch block (RBBB) and left anterior hemiblock,²⁸ hypertension and RBBB,²⁹and in patients with chest pain of unknown origin³⁰ (Figure 7b.2).

5. Management Implications of Positive Stress Echocardiograms

The ﬁnding of a positive SE carries implications for both medical management and revascularization. Because a positive test signiﬁes the presence of underlying CAD, an aggressive risk factor management approach should be adopted. In addition, the physician responsible for the patient’s care may elect to proceed to risk groups that include asymptomatic patients

with diabetes mellitus,¹⁶renal¹⁷or cardiac transplants,¹⁸ESRF¹⁹or metabolic syndrome,²⁰those with established peripheral vascular disease,²¹ and those with multiple risk factors.²²Recently, the practice of SE in screening certain high-risk groups for noncardiac surgery has become more common.¹⁵

4. Echocardiography as a Screening Tool

4.1 Prognostic Value of Resting Echocardiography

The prevalence of asymptomatic left ventricular dysfunction has been estimated at 0.9%–12.9%.²³ Resting left ventricular systolic dysfunction is a predictor of outcome when applied to asymptomatic individuals from a randomly selected population.²⁴ The likely cause of resting left ventricular systolic dysfunction is CAD and early intervention in these individuals with medical treatment such as angiotensin-convert- ing enzyme inhibitors, b-blockers, or antiplatelet agents may prevent progression to more severe degrees of heart failure, although current evidence in support of a screening program using resting echo alone is inadequate.²³

Figure 7b.2. Wall motion abnormalities during exercise echocardiography. End- systolic freeze-frame images (endocardial contour marked by dotted line, contrast with end-diastolic marked by continuous line) shows normal thickening in all walls at rest.

Postexercise images show an inducible wall motion abnormality in the anterior wall.

A4C, apical 4-chamber; A2C, apical 2-chamber.

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coronary angiography with a view to revascularization. Data supporting the latter option are limited. One positive study, the Asymptomatic Cardiac Ischemia Pilot Study³¹ enrolled 558 patients who had coronary anatomy suitable for revascularization, ischemia during exercise or pharmacologic stress testing, and at least one episode of asymptomatic ischemia during 48-hour ambulatory electrocardiogram (ECG) monitoring. Patients were angina-free or had few symptoms on therapy and were randomized to one of three treatment options: angina-guided medical treatment, ischemia-guided medical treatment, or revascularization. Results at 2-year follow-up showed that mortality was 6.6% in the angina-guided strategy, 4.4% in the ischemia- guided strategy, and 1.1% in the revascularization strategy. In a recent review, reduction of ischemia, either by medical therapy or revascularization in patients with silent myocardial ischemia was thought to be of beneﬁt.² These data justify the referral at least, of selected patients for revascularization.

6. Use of Stress Echo in High-risk Patient Groups

6.1 Multiple Risk Factors (Including Metabolic Syndrome/Obesity)

6.1.1 Clinical

As discussed in the introduction, the standard approach to the noninvasive evaluation of CAD precludes investigation of all asymptomatic patients because the probability of disease is considered low in the absence of chest pain, irre- spective of age and gender.³²However, prognostic studies of stress testing have shown that the identification of CAD increases the relative risk of these patients significantly,^33,34 even though their absolute risk remains low. Consequently, standard guidelines classify functional testing in patients with multiple risk factors to be a class IIb indication for testing. However, it must be recognized that this recommendation is restricted to definite risk factor criteria, and even favorable studies do not reflect application of standard risk scores such as the Framingham score.³⁵

6.1.2 Echocardiography

Almost all of the screening studies reported in patients with multiple risk factors have been performed with the exercise ECG. The use of exercise echocardiography has been compared with the Duke treadmill score in a recent study of 1832 patients without evidence of CAD, who were followed up over 10 years.³⁶ Although exercise provoked signiﬁcant (>0.1 mV) ST segment depression more often than wall motion abnormalities (12% versus 8%), which might suggest more false-positive results, Duke treadmill score (RR 0.9, P < .0001) and resting left ventricular (LV) dysfunction (RR 1.9, P <

Local Ischemia

Abnormal diastolic performance

Abnormal regional systolic function

ECG abnormalities

Chest Pain

RPP/Exercise Duration

Indices of Ischemia

Figure 7b.3. The ischemic cascade.The development of chest pain and electro- cardiographic (ECG) changes of ischemia occur at a greater level of cardiovascular stress than wall motion or perfusion abnormalities.

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these techniques and also for the assessment of endothelial function, see Chapters 7a and 14, respectively.

6.1.4 Appropriate Responses

A summary report from an AHA prevention conference outlined a strategy to identify high-risk asymptomatic individuals, who would be appropriate for aggressive risk-factor modiﬁcation.³⁹In accordance with ATP III⁴⁰and JNC-VII⁴¹ guidelines, high-risk asymptomatic individuals should have all cardiovascular risk factors treated and modiﬁed in an attempt at primary prevention. There are limited data to support revascularization of some patients in this category.

.04), but not ischemia at exercise echocardiography, were predictors of events, even in patients with multiple risk factors (Figure 7b.4; see color section).

6.1.3 Alternate Strategies for Screening

Myocardial perfusion scintigraphy (MPS) has been shown to be useful in this setting and particularly for the identiﬁcation of disease in rela- tives of patients with premature CAD. Its value is stronger when it is performed after a positive exercise ECG.^37,38 Electron beam computed tomography (EBCT) or multislice computed tomography, followed, depending on the results, by MPS is another possibility. For a more detailed discussion on the role of

ST No ST

ST segment Follow-up (years)

0 2 4 6 8 10

.50 .60 .70 .80 .90 1.00

Survival %

Abnormal Normal

LV dysfunction Follow-up (years)

0 2 4 6 8 10

.50 .60 .70 .80 .90 1.00

Survival %

Normal

Ischemia Follow-up (years)

0 2 4 6 8 10

.50 .60 .70 .80 .90 1.00

Survival %

High Low

Duke score Follow-up (years)

0 2 4 6 8 10

.50 .60 .70 .80 .90 1.00

Survival %

Intermed

Ischemia

Figure 7b.4. Kaplan-Meier survival curves of patients with and without ST depression, LV dysfunction, and ischemia and in each risk level of the Duke treadmill score.

(Reproduced from Marwick et al.³⁶).

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6.2 Diabetes Mellitus 6.2.1 Clinical

The problem with testing patients with multiple risk factors is that these carry varying levels of risk. In contrast, by restricting the screened group to patients with type II diabetes (>90%

of all diabetic patients), the risk of CAD is increased two- to six-fold.^50–52 There is no uniform policy regarding screening diabetic patients for CAD. Some authors suggest that

“screening would make no useful contribution to management.”⁵³ Others suggest that approxi- mately 20% of asymptomatic type II male diabetics have signiﬁcant CAD and do recommend screening in male diabetics in whom the duration of the disease is longer than 10 years or if one additional risk factor is present.⁵⁴Methods of enriching the group screened include apply- ing Framingham model to the selected population as a whole and screening only those who are high risk (i.e., those who have a >1% risk of events per year).

6.2.2 Echocardiography

It has been suggested that diabetic cardiomyopathy should be screened for using cardiac ultrasound,⁴⁷and tissue Doppler techniques may be able to identify subclinical disease.⁴⁸However, these patients show a normal stress response and therefore CAD is not an etiologic factor.⁴⁹For identiﬁcation of CAD, a number of studies, shown in Tables 7b.1a and 7b.1b, have used SE in diabetic patients. Some of these have been in symptomatic rather than asymptomatic

patients, but overall, it seems that SE is a valid and informative technique for screening diabetic patients.

6.2.3 Alternate Strategies for Screening

Other screening tests for CAD have been evaluated in asymptomatic diabetic patients. These include exercise tolerance testing (ETT), MPS, and EBCT. In a cohort of 206 patients who underwent ETT, 29% were unable to exercise sufﬁciently⁶⁴ and this has implications for the sensitivity and speciﬁcity of the test in this patient group. Other studies have screened using the combination of ETT and MPI⁴⁶ or EBCT alone.⁶⁵The use of ETT, MPI, and SE in asymptomatic diabetics⁵⁷has been compared. In this study, predictive positive value was 69% for dobutamine stress echocardiography (DSE), 75% for MPS using 201Tl single photon emission computed tomography (SPECT) and 60% for ETT. For a further discussion on the role of these techniques in this group of patients, see also Chapter 7a.

6.2.4 Appropriate Responses

All patients with diabetes should have aggressive risk-factor modiﬁcation according to American Diabetes Association guidelines.⁶⁶For those who are revascularized, even after revascularization, there is a high frequency of silent myocardial ischemia – in one study this was reported as 43%.⁶⁴ Diabetic patients tend to have more

Table 7b.1a. Diagnostic use of SE in patients with diabetes mellitus

Author Group Test used Asymptomatic Results

Bacci et al.⁵⁰ 35 DM unable to exercise DSE and CA Yes Sensitivity 21%, speciﬁcity 94%

Coisne et al.⁵¹ 49 DM and 63 nondiabetics DSE and CA Yes Positive DSE in 3 of 49 DM (conﬁrmed by angio) Elhendy et al.⁵² 1446 patients, 184 DM DSE and CA ? Sensitivity 81%, speciﬁcity 85%

Gaddi et al.⁵³ 24 DM with positive thallium DiSE and CA Yes Sensitivity 92%, speciﬁcity 100%

Grifﬁn et al.⁵⁴ 18 DM and nephropathy DSE and CA Yes 7 positive DSE with 2 positive angios Hennessy et al.⁵⁵ 52 DM for cardiac opinion DSE and CA ? Sensitivity 82%, speciﬁcity 54%

Hung et al.⁵⁶ 338 patients post-AMI, 116 DM DSE and CA ? Sensitivity 71.8%, speciﬁcity 50%

Penfornis et al.⁵⁷ 56 DM SPECT, ExECG, DSE, and CA Yes Sensitivity 69%, speciﬁcity 89%

CA, coronary angiography; DSE, dobutamine stress echo; DiSE, dipyridamole stress echo; ExECG, exercise ECG; SPECT, single photon emission computed tomography;

DM, diabetes mellitus; AMI, acute myocardial infarction.

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and the epidemic of diabetes mellitus (Figure 7b.5; http://www.usrds.org).

Disturbingly, the cardiovascular mortality in young patients on dialysis is similar to that of older patients, and several orders of magnitude greater than the general population, matched for age.⁷³

There is no consensus about how best to go about the process of detecting CAD in patients with end-stage renal disease. In many centers, some form of testing is routinely performed at the time of transplant evaluation, with the hope of decreasing the risk of surgery and also reduce the prospect of “wasting” a donated kidney if the patient were to succumb to a coronary event post-transplantation. However, the restriction of testing to this time frame does not account for the risks associated with the predialysis population, as well as those dialysis patients who are not candidates for transplant.

The only clinical tool developed to facilitate risk prediction in this population was reported by Le et al.,⁷⁴who identiﬁed three groups. Those with low risk (<0.5% per year over 4 years) were aged <50 years, nondiabetic, asymptomatic for either coronary disease or heart failure, and with a normal ECG. Intermediate risk patients (0.5%–4% annualized event rate) were also asymptomatic, but >50 years old or diabetic, and diffuse CAD than their nondiabetic counterparts

and often have poor target vessels, which may contribute to worse outcomes after revascularization. Nonetheless, the data in Table 7b.1b indi- cate that diabetes and ischemia are a potent combination in terms of provoking subsequent events, and although no strong evidence base is yet available, it seems reasonable to consider revascularization, at least for selected patients. In randomized studies comparing revascularization by either coronary bypass surgery (CABG) or percutaneous intervention (PCI), diabetic patients who undergo CABG have a survival beneﬁt over diabetics who have PCI.^76,77In addition, patients with diabetes have higher resteno- sis rates after PCI.^78,79

6.3 End-stage Renal Failure 6.3.1 Clinical

Patients with end-stage renal disease are prone to coronary events, partly because of the high prevalence of risk factors (hypertension, diabetes, dyslipidemia), and partly because uremia itself provides an atherogenic milieu.⁷² More- over, the number of patients requiring dialysis is increasing with both the aging of the population

Table 7b.1b. Prognostic use of SE in patients with diabetes mellitus

Author Group Test used Asymptomatic Result

Bates et al.⁵⁸ 53 IDDM for kidney/pancreas Tx DSE Yes Event rates 45% in those with abnormal DSE (38%) vs 6% with normal DSE Bigi et al.⁵⁹ 259 DM, 108 DSE, 151 DiSE, 120 DSE, DiSE ExECG No SE positive in 65% with FU events and

ExSE 39% without. SE negative in 35% with

FU events and 61% without.

D’Andrea et al.⁶⁰ 325 DM (128 diagnosis, 197 risk 195 DSE, 130 DiSE No 45.8% positive SE hazard ratio 2.9 for stratify) death

Elhendy et al.⁶¹ 563 DM ExSE ?No 41% ExSE positive. Event rate lower in

normal ExSE vs abnormal ExSE at 1 yr (0% vs 1.9%), 3 yr (1.8% vs 11.9%), and 5 yr (7.6% vs 23.3%) Hung et al.⁵⁶ 338 patients post-AMI, 116 DM DSE and CA ? 38.9% events in DM with positive DSE;

20% in DM with negative DSE Kamalesh et al.⁶² 239 patients, 89 DM negative DSE ? FU 25 ± 7 mo DM had higher incidence

ExSE/DSE of cardiac events (19% vs 9.7%)

Marwick et al.¹⁶ 937 DM for symptoms (42%) DSE No 165/370 with rest or stress WMA died

and FU CAD during FU (M 3.9 yr)

Sozzi et al.⁶³ 396 DM unable to exercise DSE ?No DSE abnormal in 82% abnormal vs normal DSE death rate: 1 yr 9 vs 3%

3 yr 29 vs 11% 5 yr 31 vs 24%

CA, coronary angiography; DSE, dobutamine stress echo; DiSE, dipyridamole stress echo; ExECG, exercise ECG; ExSE, exercise stress echo; DM, diabetes mellitus; Tx, transplant; FU, follow-up; WMA, wall motion abnormalities; IDDM, insulin dependent diabetes mellitus; AMI, acute myocardial infarction; SE, stress echo.

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in the normal population, reﬂecting the difﬁculties posed by attaining peak stress in these patients – many of whom are taking b- blockers or hypertensive.

Data have also been obtained regarding the prognostic implications of stress testing in patients with ESRF (Table 7b.2b). Generally, high risk (>4% annualized risk) were sympto-

matic for either coronary disease or heart failure.

6.3.2 Echocardiography

Resting echocardiography is very often abnormal in this patient group, showing either LV hypertrophy, LV enlargement, or systolic dysfunction.⁷⁵ These abnormalities are associated with adverse outcome, and many renal units perform routine resting echos on a regular basis to identify these abnormalities.

SE has also been used in ESRF patients, usually at the time of transplant evaluation.

Table 7b.2a illustrates the reported sensitivity and speciﬁcity of dobutamine echo in ESRF; it seems that its sensitivity is somewhat less than

300

250

200

150

100

50

0

0 200 400 600 800 1000 1200 1400

1978 1988 1998 2008 2018 2028

Diabetes 'Other

1978 1988 1998 2008 2018 2028 Diabetes 'Other

Incidence (in thousands) Prevalance (in thousands)

Figure 7b.5. Projected growth of the incident and prevalent ESRD populations, by primary cause of renal failure.

Table 7b.2a. Diagnostic use of DSE or thallium scans in ESRF

Study Stress Group Sensitivity (%) Speciﬁcity (%)

Boudreau et al.⁷⁶ Dip-Tl 40 patients with DM and ESRF 86 72

Marwick et al.⁷⁷ Dip-Tl 45 Tx candidates 37 73

Vandenberg et al.⁷⁸ Dip-Tl 41 Tx patients 53 73

Dahan et al.⁷⁹ Dip-Tl 60 asymptomatic HD patients 92 89

Reis et al.⁸⁰ DSE 97 ESRF patients 95 86

Herzog et al.⁸¹ DSE 50 Tx candidates 75 76

DM, diabetes mellitus; ESRF, end stage renal failure; Tx, transplant; Dip T1, dipyridamole thallium; HD, haemodialysis; DSE, dobutamine stress echo.

Table 7b.2b. Prognostic implications of DSE in ESRF

Study Stress Group Outcomes

Reis et al.⁸⁰ DSE 97 Tx and HD PV negative test 97%

patients over 12 mo Brennan et al.⁸² DSE 47 ESRF patients PV negative test 95%

over 20 mo Marwick et al.¹⁹ DSE 193 ESRF patients Predicted early but

not late events DSE, dobutamine stress echo; Tx, transplant; HD, haemodialysis; PV, predictive value; ESRF, end stage renal failure; MO, months.

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these patients are debilitated and pharmacologic stress testing is necessary. The presence of a normal scan does imply a favorable prognosis in this patient group, although the warranty of a normal test result (2 years) is somewhat shorter than in other circumstances (Figure 7b.6; see color section). Ischemia is associated with an adverse outcome in ESRF, as in other diseases.

6.3.3 Alternate Strategies for Screening

Other screening tests for CAD have also been evaluated in ESRF. From a diagnostic standpoint, dipyridamole thallium scanning has a somewhat lower speciﬁcity (probably reﬂecting false posi- tives because of LV hypertrophy) (Table 7b.2a).

Various explanations for its lower sensitivity have been proposed – abnormalities or myocardial perfusion and disturbances of adenosine metabolism being the most plausible. The prognostic ﬁndings have also been somewhat vari- able (Table 7b.2c).

A number of other markers of risk have been reported in ESRF. These include biomarkers of both subclinical cardiac damage (e.g., troponin) and vascular inﬂammation (e.g., C-reactive protein), genetic markers, and vascular function parameters (e.g., pulse wave velocity). Coronary calcium is often observed in ESRF – being pri- marily associated with age, duration on dialysis, and disturbances of calcium metabolism,⁹¹and does not seem to be a good surrogate for CAD in this group.

0.00 10.00 20.00 30.00 40.00

Months of Follow-up LR chis q = 2.4, p > 0.4

Normal Scar

Nondiagnostic Ischemia 1.00

0.90 0.80 0.70 0.60 0.50 0.40 0.30 0.20 0.10 0.00

Survival Free of Total Event

Figure 7b.6. Event-free survival of patients with end-stage renal disease.

Curves reﬂect outcomes with ischemia, scar, nondiagnostic, and normal dobutamine echocardiography. (Reproduced from Marwick et al.¹⁹).

Table 7b.2c. Prognostic ﬁndings of thallium scanning in renal patients

Study Stress agent Group Outcomes

Morrow et al.⁸³ Ex-T1 85 Tx and HD patients T1 predictive but not more than Hx CAD/ECG Brown et al.⁸⁴ Dip-T1 65 DM and non-DM Tx patients Ischemia and EF predicted outcome Marwick et al.⁷⁷ Dip-T1 45 Tx candidates T1 did not predict outcome Camp et al.⁸⁵ Dip-T1 40 DM Tx candidates Only patients with T1 defects had events Holley et al.⁸⁶ Ex-T1 141 DM Tx candidates T1 did not predict perioperative risk Derfler et al.⁸⁷ Dip-T1 59 asymptomatic/symptomatic ESRF T1 predicted events, not death Brown et al.⁸⁸ Ex-T1 103 asymptomatic ESRF Sensitivity 88%, specificity 70% for events Le et al.⁷⁴ Ex-T1 95 high-risk Tx patients T1-ischemia/scar predicted outcomes Lewis⁸⁹ Ex-T1 112 high risk pts T1-ischemia/scar predicted outcomes Vandenberg et al.⁷⁸ Dip-T1 41 Tx patients Outcome same with + or - scan Heston et al.⁹⁰ Dip-T1 95 Tx patients; T1 and neural net Sensitivity 82%, specificity 77% for events

Dahan et al.⁸⁷⁹ Dip-T1 60 asymptomatic HD patients Sensitivity 92%, speciﬁcity 89% for CAD; 3 yr FU: NPV 91%, PPV 47%

T1, thallium scintigraphy; HD, hemodialysis; CAD, coronary artery disease; DM, diabetes mellitus; EF, ejection fraction; Tx, transplant; NPV, negative predictive value;

PPV, positive predictive value; Ex, exercise; Dip, dipyridamole; HX, history; FU, follow up; ESRF, end stage renal failure.

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6.3.4 Appropriate Responses

Patients with renal disease should have cardiovascular risk-factor modification⁹⁹ whether or not they have established cardiac disease. For patients with positive stress echoes who undergo coronary angiography, there is a risk of further impairment of renal reserve by contrast medi- ated nephropathy, particularly in those patients who are not dialysis dependent.¹⁰⁰ A recent review has suggested that patients with ESRF benefit from coronary revascularization either by CABG or PCI.¹⁰¹However, large randomized controlled trial data are required to support this and the value of this in a screening group needs to be defined.

6.4 Cardiac Transplants 6.4.1 Clinical

In patients with cardiac transplants, the risk of CAD is increased and the prevalence 5 years posttransplantation has been estimated at 42%.⁹⁶ Denervation of the transplanted heart removes warning symptoms of CAD such as

angina and so screening for CAD is usually performed by coronary angiography. An alternative approach may be to use noninvasive methods to predict cardiac events, and some centers, however, have abandoned routine angiography.⁹⁷

6.4.2 Echocardiography

A number of studies shown in Tables 7b.3a and 7b.3b have used SE in cardiac transplant patients. Recently recorded levels of sensitivity have been acceptable. The disease is often a diffuse process, so that angiography alone is sub- optimal as the gold standard.

6.4.3 Alternate Strategies for Screening

MPS could be a useful alternative but other noninvasive tests, such as exercise testing or radionuclide ventriculography, have not been shown to be useful as screening tests.^112,113EBCT is emerging as a promising technique^114,115 for assessment of CAD after transplantation.

Table 7b.3a. Accuracy of DSE for diagnosis of CAD in cardiac transplant patients

Author Group Test used Sensitivity (%) Speciﬁcity (%)

Akosah et al.⁹⁸ 41 DSE and CA 95 55

Akosah et al.⁹⁹ 82 (45 had CA) DSE induced angina and CA 33 95

Bacal et al.¹⁰⁰ 39 24-h Holter, thallium scintigraphy, ETT, DSE 64 91

Ciliberto et al.¹⁰¹ 68 DSE and CA 100 87

Derumeaux et al.¹⁰² 37 DSE and CA at 37 and 56 mo post-OCT (37 mo) 65, (56 mo) 92 95, 73

Derumeaux et al.¹⁰³ 55 DSE and CA 85 93

Derumeaux et al.¹⁰⁴ 37 DSE and CA 86 91

Gunther et al.¹⁰⁵ 20 DSE and CA 50 100

Herregods et al.¹⁰⁶ 28 DSE and CA 0 100

Spes et al.¹⁰⁷ 46 DSE, IVUS, and CA (CA) 83, (IVUS) 79 56, 83

Spes et al.¹⁰⁸ 80 DSE, IVUS, and CA 85 71

Spes et al.¹⁰⁹ 109 DSE, IVUS, and CA 85 82

CA, coronary angiography; DSE, dobutamine stress echo; IVUS, intracoronary ultrasound; OCT, orthotopic cardiac transplant; ETT, exercise treadmill testing;

MO, months.

Table 7b.3b. Prediction of events using DSE in cardiac transplant patients

Author Group Test used Result Outcome

Akosah et al.⁹⁸ 77 DSE DSE positive in 57 33% had cardiac events in 2 yr FU

Akosah et al.⁹⁹ 22 DSE and CA 11 had persistent WMA 8/11 had events over mean FU 32 mo; no events in 11 patients with negative DSE

Ciliberto et al.¹⁰¹ 68 DSE and CA 21 positive DSE 11/21 had cardiac events Lewis et al.¹¹¹ 63 DSE 21 positive DSE, 42 negative DSE 5 events in 21, 1 event in 42 DSE, dobutamine stress echocardiography; CA, coronary angiography; WMA, wall motion abnormalities; MO, months.

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a routine test. In patients with a history of unexplained dyspnoea or previous heart failure diagnosis without an estimation of ejection fraction, the test may indeed guide perioperative therapy, especially regarding ﬂuid management.

Unfortunately, the value of routine echocardiography seems restricted to the prediction of perioperative heart failure, with a slightly higher frequency of sudden death in those with LV dysfunction.¹²³ Moreover, although the test is sometimes performed to identify silent ischemic heart disease, it is ischemia that determines risk – much more than infarction – so that patients with clinical risk variables warrant a stress test, not a resting echocardiogram.

SE is widely performed in at-risk patients undergoing major surgery. Because many such patients are unable to exercise, either because of peripheral vascular disease or other comorbidity, pharmacologic stress echo is usually performed – the most widely used stressor being dobutamine. Cardiac complications occur very rarely in those patients with normal studies, usually expressed as a very high negative predictive value (Table 7b.4).

The frequency of events in those with positive tests is about 20% overall (Table 7b.4) and may be substratiﬁed based on the number of clinical risk predictors (Figure 7b.8¹³⁹).

An asymptomatic patient may score up to three Eagle factors for age, diabetes mellitus, and ECG evidence of silent infarction.

The other determinant of outcome in patients with a positive stress echocardiogram is the ischemic threshold,¹²¹which is the heart rate at which ischemia is ﬁrst identiﬁed. Its importance

6.4.4 Appropriate Responses

Revascularization in patients with cardiac transplants is complicated by the nature of the diffuse disease in graft coronary disease. For this reason, the use of CABG is limited.¹¹⁶PCI is more suc- cessful¹¹⁷ and should be considered for severe lesions.

6.5 Noncardiac (Vascular) Surgery 6.5.1 Clinical

Patients undergoing surgery for peripheral vascular disease represent a high-risk group for silent coronary disease, even if they are asymptomatic.¹¹⁸From the standpoint of perioperative risk evaluation, the clinical risk factors as designated by Eagle et al.¹¹⁹usually determine the use of other testing to designate risk, because they are predictive of perioperative events.¹²⁰ Although patients without these predictors may very well have coronary disease and occasionally have positive studies (Figure 7b.7¹²¹), they rarely have events.¹²²

The paucity of data regarding the screening of patients without these risk predictors reﬂects the age and comorbidity of this patient group, which tend to focus the process of screening on perioperative rather than long-term risk.

6.5.2 Echocardiography

Resting echocardiography is often requested in this patient group but has limited value as

0 100

1 or 2 179

3 or more 21 DSE

Stress WMAs Cardiac Events Major Events

300 patients

0 3 8 1 5

1

1 0 0

0

0 6 14 5

high 9

high 21 low

3

low 28

high 4

low 7 neg

100

neg 130

neg 10 pos

12

pos 49

pos 11 Clinical

Risk Variables

Figure 7b.7. Clinical variables and DSE results for perioperative outcome. WMAs, wall motion abnormalities; DSE, dobutamine stress echocardiography.

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mandates sequential videotape or digital record- ing of wall motion during the study; development of ischemia at a heart rate <70% of predicted maximum identiﬁes the patient as being at particularly high risk of perioperative events – as high as 30%–50% in the presence of three or more risk factors. Whereas the use of dobutamine stress facilitates the acquisition of data at intermediate stages, gauging the time of onset of abnormal wall motion remains sub- jective. Interestingly, the extent of ischemia, although not a predictor of perioperative outcome, is a determinant of long-term outcome.¹³³

6.5.3 Alternate Strategies for Screening

As mentioned above, exercise testing is rarely used in this patient population because the

ability to exercise maximally is compromised by their underlying disease.

MPS has also been used extensively in risk evaluation of patients undergoing noncardiac surgery (see also Chapter 9b). The results of these studies have been closely analogous to those obtained with stress echo, with a very high negative predictive value and a positive predictive value usually in the 20% range. With this test, the extent of ischemia has been identiﬁed as an important determinant of risk.¹³⁴Stress echo and nuclear approaches have been compared in head-to-head studies¹³⁵ and meta-analyses.¹³⁶ The results of these studies have shown equiva- lence between the two tests.

6.5.4 Appropriate Responses

In the diagnostic setting, the usual response to a positive stress echo is the performance of coronary angiography. This needs careful considera- tion in the vascular surgery group for several reasons. First, the risk of the procedure is greater than usual, with respect to both complicated atheroma and concomitant disease, which may, for example, increase the risk of renal sequelae.

Second, the evidence to support percutaneous revascularization as a means of reducing perioperative risk is scant, and although there are some data in favor of selective surgical revascularization,¹³⁷ many such patients are not good candidates for cardiac surgery on the basis of age or comorbidity. However, b-adrenoceptor blockers have been shown to be effective,¹³⁸although

Table 7b.4. Predictive value of SE in perioperative outcomes n PPV (%) NPV (%) Events Lane et al.¹²⁴ 57 21 100 CD, MI, UA Poldermans et al.¹²¹ 300 38 100 CD, MI, UA, HF Lalka et al.¹²⁵ 60 29 95 CD, MI, UA Davila-Roman et al.¹²⁶ 93 83 100 CD, MI, UA, HF Eichelberger et al.¹²⁷ 70 19 100 MI, UA

Langan et al.¹²⁸ 74 17 100 MI

Tischler et al.¹²⁹ 109 78 99 CD, MI, UA Rossi et al.¹³⁰ 110 23 94 CD, MI, UA, HF Pasquet et al.¹³¹ 129 23 95 CD, MI, UA Sicari et al.¹³² 509 28 99 CD, MI, UA PPV, positive predictive value; NPV, negative predictive value; CD, cardiovascular death; MI, myocardial infarction; UA, unstable angina; HF, heart failure.

35 30 25 20 15 10 5 0

No ischemia Low score, ischemia

High score, high threshold

High score, low threshold

% events

Figure 7b.8. Risk of perioperative events in patients with and without ischemia at high and low threshold and clinical risk variables.

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Association Task Force on Practice Guidelines (Com- mittee on Coronary Angiography) developed in col- laboration with the Society for Cardiac Angiography and Interventions. Circulation 1999;99:2345–2357.

5. Sicari R, Pasanisi E, Venneri L, Landi P, Cortigiani L, Picano E. Stress echo results predict mortality: a large- scale multicenter prospective international study. J Am Coll Cardiol 2003;41:589–595.

6. Marwick TH, Case C, Sawada S, et al. Prediction of mortality using dobutamine echocardiography. J Am Coll Cardiol 2001;37:754–760.

7. Pizzuto F, Voci P, Romeo F. Value of echocardiography in predicting future cardiac events after acute myocardial infarction. Curr Opin Cardiol 2003;18:378–384.

8. Butler JR. Economic evaluations of screening pro- grams: a review of methods and results. Clin Chim Acta 2002;315:31–40.

9. Myerburg RJ, Kessler KM, Castellanos A. Sudden cardiac death – epidemiology, transient risk, and intervention assessment. Ann Intern Med 1993;119:

1187–1197.

10. Kannel WB, Doyle JT, McNamara PM, Quickenton P, Gordon T. Precursors of sudden coronary death.

Factors related to the incidence of sudden death.

Circulation 1975;51:606–613.

11. Diamond GA, Forrester JS. Analysis of probability as an aid in the clinical diagnosis of coronary-artery disease. N Engl J Med 1979;300:1350–1358.

12. Elhendy A, Shub C, McCully RB, Mahoney DW, Burger KN, Pellikka PA. Exercise echocardiography for the prognostic stratiﬁcation of patients with low pretest probability of coronary artery disease. Am J Med 2001;

111:18–23.

13. Hennessy TG, Codd MB, Kane G, McCarthy C, McCann HA, Sugrue DD. Dobutamine stress echocardiography in the detection of coronary artery disease: importance of the pretest likelihood of disease. Am Heart J 1997;134:685–692.

14. Wilson PW, D’Agostino RB, Levy D, Belanger AM, Silbershatz H, Kannel WB. Prediction of coronary heart disease using risk factor categories. Circulation 1998;97:1837–1847.

15. Eagle KA, Brundage BH, Chaitman BR, et al. Guide- lines for perioperative cardiovascular evaluation for noncardiac surgery. Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Perioperative Cardiovascular Evaluation for Noncardiac Surgery).

J Am Coll Cardiol 1996;27:910–948.

16. Marwick TH, Case C, Sawada S,Vasey C, Short L, Lauer M. Use of stress echocardiography to predict mortality in patients with diabetes and known or suspected coronary artery disease. Diabetes Care 2002;25:

1042–1048.

17. Herzog CA, Marwick TH, Pheley AM, White CW, Rao VK, Dick CD. Dobutamine stress echocardiography for the detection of signiﬁcant coronary artery disease in renal transplant candidates. Am J Kidney Dis 1999;33:1080–1090. With Dussol B, Bonnet JL, Sampol J, Savin B, De La FC, Mundler D, et al. Prognostic value of inducible myocardial ischemia in predicting cardiovascular events after renal transplantation. Kidney Int 2004;66:1633–1639.

18. Akosah KO, McDaniel S, Hanrahan JS, Mohanty PK.

Dobutamine stress echocardiography early after heart transplantation predicts development of allograft

not in the highest-risk patients. Therefore, the allocation of risk on the basis of clinical status and stress testing results may facilitate selection of individualized therapy.

7. Conclusion

Echocardiography provides useful information for high-risk asymptomatic patients. When com- bined with stress, a powerful prognostic tool is available that can unmask previously undiagnosed CAD. The application of this to screening is constrained by overall low disease probability in unselected asymptomatic patients, but the use of clinical tools, such as the Framingham risk score, can deﬁne a subgroup, which will be enriched with high-risk individuals.

We have examined the role of SE and other imaging modalities in various high-risk subgroups. Overall, SE seems to have a good predictive value comparable to that of MPS and in certain cases may avoid the need for coronary angiography. For those who have abnormalities on a noninvasive imaging test and are asymptomatic, a management plan needs to be deﬁned.

This includes a choice of addressing cardiac risk factors, or invasive assessment of coronary anatomy by angiography with a view to possible revascularization if necessary. In many of the high-risk subgroups we have discussed, the deci- sion to proceed to revascularization is hampered by the lack of large randomized trials to support this approach.Although SE and MPS can provide prognostic data in high-risk subgroups, further clariﬁcation with multicenter studies is required to assess under what circumstances revascularization can alter prognosis in high-risk patients who are truly asymptomatic.

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