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Keywords:

  • chronic renal failure;
  • dobutamine echocardiography;
  • prognosis;
  • risk stratification

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgements
  9. References

Marwick TH, Lauer MS, Lobo A, Nally J, Braun W (Cleveland Clinic Foundation, Cleveland, USA). Use of dobutamine echocardiography for cardiac risk stratification of patients with chronic renal failure. J Intern Med 1998; 244: 155–61.

Objectives

This study sought to define the value of dobutamine echocardiography (DbE) for cardiac risk stratification in patients with chronic renal failure (CRF).

Design

Outcome study correlating results of DbE with late cardiac events in patients with CRF.

Setting

Academic medical centre.

Subjects

All patients with CRF (serum creatinine > 2.5 mg dL−1) undergoing DbE were studied; we analysed 193 consecutive patients (aged 63 ± 13 years, 73 men).

Interventions

A standard dobutamine–atropine stress was administered until attainment of peak dose, or the development of severe ischaemia or side-effects. The electrocardiogram (ECG) and echocardiogram were obtained before, during and after stress. Ischaemia was identified by new or worsening wall-motion abnormalities with stress.

Outcome measures

Patients were followed up after 38 ± 14 months for cardiac death, myocardial infarction or coronary disease progression requiring revascularization.

Results

DbE demonstrated ischaemia in 36 patients (19%), scar in 36 (19%) and a normal study in 121 patients. The heart-rate response to dobutamine was submaximal (< 85% age-predicted heart rate) in the absence of wall-motion abnormalities in 69 patients (36%), 54 of whom completed the protocol. Follow-up data were complete in 191 patients (99%); cardiac events occurred in 33 patients (17%), including 17 with cardiac death, 7 with infarction, and 9 requiring late revascularization. Spontaneous events occurred in 7 patients with ischaemia, 3 with scar (8%), 11 with a nondiagnostic study (16%) and 3 patients with a normal study (6%). Over the entire follow-up, the event-free survival in patients with ischaemia (66%) was markedly lower than those without ischaemia (84%, P= 0.006). However, the event rate in patients with nonischaemic responses increased from 8% to 16% between 24 and 40 months, and whilst ischaemia was an independent predictor of outcome at 24 months, it was not at 40 months.

Conclusions

In patients with CRF, the identification of ischaemia at DbE is associated with a significant risk of adverse cardiac events. Patients with nonischaemic scans have a low frequency of events over short-term follow-up, but this increases at later follow-up. These later events may reflect progressive coronary disease, attributable to the atherogenic milieu of these patients, and imply that repeated testing may be required to maintain cardiac risk stratification in patients with CRF.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgements
  9. References

Cardiovascular complications have been recognized for over 10 years as the major source of morbidity and mortality in patients undergoing dialysis and transplantation for end-stage renal failure [ 1]. In renal transplant candidates with diabetes and known coronary artery disease (CAD), the 2-year mortality rate has been reported in the 50% range without coronary revascularization [ 2, 3]. Similarly, approximately 40% of deaths in patients on dialysis are due to cardiovascular complications [ [4][5][6]4–7]. Moreover, the identification and revascularization of renal transplantation candidates now appears to reduce cardiac event rates [ 8].

The recognition of CAD in patients with chronic renal failure (CRF) is challenging. Ischaemia is often silent, because debilitated patients may fail to exercise sufficiently to provoke angina, and many have diabetes. Most of these patients are unable to exercise maximally because of deconditioning, and the accuracy of the exercise electrocardiogram (ECG) is often compromised by left ventricular hypertrophy. The accuracy of dipyridamole stress myocardial perfusion imaging has been debated [ 9, 10], and may also be limited by hypertrophy. The accuracy of stress echocardiography does not appear to be substantially influenced by hypertrophy or hypertension [ 11, 12], and initial data suggest that dobutamine echocardiography (DbE) is accurate for the detection of CAD in this setting [ 13].

As the atherogenic process may be accelerated in patients with renal disease, especially after transplantation [ 14], surveillance for coronary disease may also be an important consideration. Dobutamine echocardiography has been shown to provide short-term cardiac risk stratification, but its ability to evaluate prognosis over the medium term is not known. This study sought to evaluate the prognostic value of this test for the prediction of cardiac events in patients with CRF.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgements
  9. References

Patient selection

A total of 193 consecutive patients with renal impairment (serum creatinine > 2.5 mg dL−1) undergoing dobutamine echocardiography for risk stratification were enrolled into the study. The mean age was 63 ± 13 years, and the group included 120 men and 59 patients (31%) with a previous myocardial infarction, and 67 with chest pain (35%), which was typically anginal in 19. A total of 182 patients (94%) were in functional classes 1 and 2.

All patients in the study had major risk factors for coronary disease; 155 (80%) had hypertension, 82 (42%) had diabetes, 86 (45%) had hyperlipidaemia and 50 (26%) were actively smoking. The aetiology of renal impairment was unknown in the majority; the most frequent known aetiology was diabetes, followed by renal stone disease (n= 16) and renal artery stenosis (n= 8). Dobutamine echocardiography was performed to screen for the development of coronary disease in patients being evaluated for possible dialysis and transplantation, or in patients who were already on dialysis (n= 10) or had transplanted kidneys (n= 31).

Dobutamine stress echocardiography

Dobutamine stress was performed using a standard dobutamine–atropine protocol [ 15]. After preparation of the patient in the usual fashion for stress testing, an intravenous cannula was inserted into a proximal arm vein. Resting echocardiographic images were acquired in the parasternal long and short axis and apical two- and four-chamber views. These images were stored on videotape, as well as being acquired in digital format online. With the patient under continuous clinical, electrocardiographic and echocardiographic monitoring, dobutamine was infused at doses of 5, 10, 20, 30 and 40 mcg kg−1 min−1. The test was terminated in the presence of severe chest pain or ischaemia, severe side-effects or the completion of the protocol. If the patient failed to achieve the target heart rate (85% of age-predicted maximum) at a dose of 40 mcg kg−1 min−1 in the absence of these endpoints, atropine (0.25 mg min−1) was administered to a total of 1 mg, at the discretion of the physician performing the test.

Following the test, a physician blinded to the clinical data interpreted the ECG and echocardiographic responses. Ischaemia was identified at electrocardiography in the presence of ≥ 0.1 mV of ST segment depression at 0.08 ms after the J point. Patients with resting electrocardiograms demonstrating extensive repolarization abnormalities, including those due to left ventricular hypertrophy and left bundle branch block, were excluded from ECG analysis. Echocardiographic images were interpreted in a digitized quad-screen display. A normal scan was identified if the patient stressed maximally (to > 85% predicted heart rate) and no wall-motion abnormalities were present at rest or with stress. However, negative tests at a submaximal heart rate were identified as nondiagnostic. Ischaemia was identified in the presence of a new or worsening wall-motion abnormality. Infarction was diagnosed in the presence of akinesis or dyskinesis at rest. Ischaemia was identified in the presence of a new or worsening wall-motion abnormality; studies showing the absence of ischaemia (normal, nondiagnostic or scar) were classified as nonischaemic.

Follow-up

Patients were followed up by clinic visit or by telephone at an interval of 38 ± 14 months following dobutamine echocardiography. Record was kept of the occurrence and timing of cardiac death, myocardial infarction or late revascularization. Hospital or physician records were used to designate the cause of death, which was ascribed to cardiac causes if a cardiac illness provoked the final presentation. Myocardial infarction was identified as an endpoint if this was diagnosed by the physicians caring for the patient, based upon history, cardiac enzymes and ECG changes. Together, cardiac death and myocardial infarction were classified as spontaneous cardiac events. Late revascularization was defined by the performance of coronary angioplasty (PTCA) or bypass surgery > 3 months after the original stress test, reflecting new or progressive symptoms. Total cardiac events included spontaneous events and late revascularization.

Statistical analysis

The statistical analyses included descriptive statistics (mean and standard deviation of continuous variables, and frequency and percentage of categorical variables), Kaplan–Meier analysis, and a Cox proportional hazards model. Differences between survival curves were compared with the log-rank test. In all analyses, P-values < 0.05 were considered to be statistically significant. Kaplan–Meier plots and Cox regression analyses were performed using the SAS 6.12 statistical package (SAS Inc., Cary, NC, USA).

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgements
  9. References

Dobutamine response

Blood pressure increased from 153 ± 126 to 156 ± 34 mmHg and heart rate increased from 75 ± 14 to 125 ± 21 beats min−1 after dobutamine stress. The heart-rate response to dobutamine was submaximal (< 85% age-predicted maximum heart rate) in the absence of wall-motion abnormalities in 69 patients (36%), most of whom (54 patients) completed the protocol. Side-effects were relatively rare; 6 patients had the test stopped prematurely due to chest pain, and 7 stopped at a submaximal dose because of the development of hypotension. No major or life-threatening side-effects occurred.

Dobutamine echocardiograms were interpreted in all 193 patients. A normal study was reported in 121 patients (63%). Of these 121 patients, 69 (36%) had a normal study at a submaximal heart rate, and were therefore identified as nondiagnostic. Resting wall-motion abnormalities alone were present in 36 patients (19%), and the remaining 36 patients (19%) had ischaemia, either alone or in combination with scar (n= 15). Patients showing an ischaemic response also had angina (28%) and ST segment depression (22%) provoked by dobutamine. Angina and ST depression occurred less frequently in patients with resting wall-motion abnormalities alone (8% and 3% respectively) or a normal response (7% and 4%). The nondiagnostic group had an intermediate incidence of chest pain (18%) and ST segment changes (7%), which was not significantly different from the frequency in the ischaemic group.

Prognostic evaluation

A total of 191 patients (99%) were followed up over 38 ± 14 months. Cardiac events occurred in 33 patients (18%) including 17 cardiac deaths, 7 myocardial infarctions and 9 patients revascularized for unstable angina. The cardiac outcomes of patients in the groups with ischaemia, resting wall-motion abnormalities, and normal and submaximal tests are summarized in Table 1. Over the follow-up period, patients with ischaemia had a higher event rate than the remainder (log-rank chi-square 7.5, P= 0.006) ( Fig. 1). The nondiagnostic group had an intermediate event rate, although even with separate analysis of each diagnosis ischaemia was significantly associated with adverse outcome (log-rank chi-square 8.9, P= 0.03).

Table 1.  Cardiac events in 191 patients with follow-up, who had ischaemia, scar, normal and nondiagnostic results at dobutamine echocardiography Thumbnail image of
image

Figure 1. Event-free survival of patients with and without ischaemia over the entire follow-up period.

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The normal group had a low event rate of only 4% within 2 years of the test ( Fig. 2), but this increased to 10% at 40 months. Likewise, the event rate in the combined nonischaemic group increased from 8% to 16% between 24 and 40 months, reflecting events in both the scar and the nondiagnostic groups.

image

Figure 2. Event-free survival of patients with ischaemia, scar, nondiagnostic and normal dobutamine echocardiograms over the first 2 years of follow-up.

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In a univariate comparison of patients with and without cardiac events ( Table 2), the clinical variables of prior myocardial infarction, revascularization and active nitroglycerin use, but not symptom status, risk factors or medical therapy, were predictors of recurrent events. Of the stress testing variables ( Table 3), the presence of ischaemia was related to outcome, in contrast to haemodynamic responses to dobutamine. In a Cox model which adjusted for age and prior revascularization, the presence of ischaemia was an independent predictor of events at 24 months (relative risk 3.43, 95% confidence interval 1.27–9.27, P= 0.02) but not at 40 months (relative risk 1.67, 95% confidence interval 0.76–3.70, P= 0.20). Similarly, the combination of ischaemia and a submaximal heart-rate response predicted events at 24 months (relative risk 7.99, 95% confidence interval 1.84–34.63, P= 0.006) but not at 40 months (relative risk 1.98, 95% confidence interval 0.94–4.17, P= 0.07).

Table 2.  Clinical correlates of cardiac events (cardiac death, myocardial infarction, late revascularization) Thumbnail image of
Table 3.  Dobutamine stress correlates of cardiac events (cardiac death, myocardial infarction, late revascularization) Thumbnail image of

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgements
  9. References

The findings of this study are that nondiagnostic DbE responses are common in patients with chronic renal failure, and that the predictive value of DbE may be compromised by the performance of submaximal stress. Nonetheless, patients with ischaemia have the greatest risk of cardiac events. The finding of a normal scan confers a low risk within the first 2 years, but the number of events occurring in patients with normal scans increases after this time.

Screening for coronary disease in patients with CRF

Cardiovascular (predominantly coronary) complications are the major source of mortality in patients undergoing both dialysis and transplantation [ [1][2][3][4][5][6]1–7]. As surgical revascularization of the heart may be performed effectively in these patients, attempts are made to identify coronary disease and perform myocardial revascularization in order to reduce cardiac risk [ 8].

However, the clinical history and exercise ECG are of limited value in the detection of coronary disease in this group. Performance of routine coronary angiography on patients undergoing evaluation for dialysis and transplantation has identified significant stenoses in 25–32% of patients [ 8, 16]. Nonetheless, this approach is expensive and presents risks with respect to dye exposure, which may precipitate dialysis dependence in a patient with poorly compensated end-stage renal failure.

Unfortunately, the usual diagnostic methods for the identification of coronary disease have proven to be problematic in patients with end-stage renal failure. The symptomatic status of these patients is unreliable, because of reduced exercise capacity (which may preclude the provocation of ischaemia with exercise), and because of autonomic neuropathy in diabetic patients (which may lead to ischaemia being clinically silent). Routine treadmill exercise testing has also not been efficacious in this group, who have a high prevalence of factors which contribute to nondiagnostic exercise ECG results, such as left ventricular hypertrophy, repolarization abnormalities due to electrolyte disturbances, and left bundle branch block. Indeed, an adequate level of exercise can be attained in only about 10% of patients [ 17], and this has also compromised the accuracy of exercise thallium imaging [ 18]. Pharmacological stress techniques offer a means of circumventing these problems with standard noninvasive tests for the diagnosis of coronary disease. However, whilst dipyridamole stress myocardial perfusion imaging has proven efficacious in the risk stratification of patients undergoing vascular surgery, its role in the setting of renal disease is controversial [ 9, 10].

Use of dobutamine echocardiography in chronic renal failure

The results of this study indicate that dobutamine echocardiography is a feasible diagnostic technique in patients with renal disease, although somewhat limited by the frequency of nondiagnostic tests. Causes of submaximal stress are numerous, but use of antihypertensive and anti-anginal agents (especially beta adrenoceptor and calcium channel blockers) is an important limitation in this group. Interestingly, the frequency of dose-limiting side-effects was no greater in this study than in an unselected group [ 19]. Dobutamine stress protocols may provoke hypotension through various mechanisms [ 20], and this may be accentuated in the presence of volume depletion, for example if the test is performed after dialysis. However, with appropriate timing of DbE in this study, hypotension was not a common cause of premature termination of the test.

In patients not suffering from renal impairment, dobutamine echocardiography has been found to be an accurate technique for the identification of coronary artery disease in individuals who are unable to exercise [ 21, 22]. The independence of stress echocardiography from the effects of left ventricular hypertrophy and hypertension [ 11, 12] is attractive in patients with renal disease. Moreover, dobutamine echocardiography has the attraction of being able to document resting left ventricular function and the severity of left ventricular hypertrophy, both of which are prognostically important factors in the setting of end-stage renal failure. Unfortunately, the ECG component of the stress is insensitive for the diagnosis of coronary disease [ 23], and this is probably even more marked in patients with renal disease and left ventricular hypertrophy.

Dobutamine echocardiography has been shown to predict subsequent cardiac events in patients with stable coronary disease [ 24]. In patients with atherosclerotic vascular disease, amongst whom coronary artery disease is highly prevalent [ 25], risk stratification with dobutamine echocardiography has been shown to predict peri-operative cardiac events [ 26, 27], as well as long-term outcome [ 28]. However, recent data suggest that the predictive power of dobutamine echocardiography is compromised by failure to attain maximal stress, which is itself a risk factor for subsequent cardiac events [ 29]. Submaximal stress responses to dobutamine are quite frequent in the renal failure population, and coronary disease may be more progressive in these patients than in other groups studied from the prognostic standpoint. These aspects indicate the need for particularly careful analysis of clinical and stress data in the use of dobutamine echocardiography for risk stratification in patients with end-stage renal disease.

Conclusions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgements
  9. References

Coronary disease is an important source of morbidity in patients with renal impairment, and cardiac risk stratification has been problematic in this group. Dobutamine stress echocardiography is a promising tool for the detection of coronary disease in this situation. Provided that the patient is maximally stressed, the absence of ischaemia is predictive of a favourable initial course. Repeated testing may be required to ensure ongoing risk stratification because of the presence of aggressive coronary artery disease in this patient group.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgements
  9. References

The authors gratefully acknowledge the advice of Eric J. Topol MD, the secretarial help of Mary Celano, and the support of the sonographers, fellows and staff of the Echocardiography Laboratory.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgements
  9. References
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