Prognostic value of stress myocardial perfusion imaging using adenosine triphosphate at the beginning of haemodialysis treatment in patients with end-stage renal disease

Hiroki Hase1, Nobuhiko Joki1, Hiroyasu Ishikawa1, Hiroshi Fukuda2, Yoshihiko Imamura3, Tomokatsu Saijyo1, Yuri Tanaka1, Yasunori Takahashi1, Yoji Inishi1, Masato Nakamura2 and Masao Moroi2

1Division of Nephrology and 2Division of Cardiology, Department of Internal Medicine, Toho University Ohashi Hospital, Tokyo and 3Division of Dialysis and Nephrology, Nissan Tamagawa Hospital, Tokyo, Japan

Correspondence and offprint requests to: Hiroki Hase, MD, Division of Nephrology, Third Department of Internal Medicine, Toho University Ohashi Hospital, 2-17-6 Meguro-ku, Tokyo 153-8515, Japan. Email: hiroki{at}oha.toho-u.ac.jp



   Abstract
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. Non-invasive detection of coronary artery disease (CAD) remains difficult in patients with end-stage renal disease (ESRD). This study evaluated the ability of pharmacologic stress myocardial perfusion imaging to predict cardiac events in patients with ESRD.

Methods. A prospective study was carried out in 49 consecutive patients with ESRD. Thallium-201 single photon emission computed tomography (SPECT) using high-dose adenosine triphosphate (ATP) was performed within 1 month of the beginning of haemodialysis. The study end-point was a cardiac event or the 1-year anniversary of the SPECT study.

Results. Twenty-four patients (17 diabetics, 57% and seven non-diabetics, 37%) had myocardial perfusion defects. The remaining 25 patients had normal perfusion images. Fifteen patients had non-fatal cardiac events and two patients died of a cardiac cause. All patients who had non-fatal cardiac events underwent myocardial revascularization and survived until the end of follow-up. The 1-year cardiac event-free survival rate was 34% among patients with perfusion defects and 96% among patients without perfusion defects (P<0.001). The presence of a myocardial perfusion defect was the only independent predictor of 1-year cardiac events both in overall (HR, 49.91; 95% CI, 5.15–484.00; P<0.001) and in diabetic patients (HR, 33.72; 95% CI, 2.96–383.5; P = 0.005). Diabetes and an increased C-reactive protein were associated with the progression of CAD.

Conclusions. Normal myocardial perfusion imaging by stress thallium-201 SPECT using high-dose ATP performed within 1 month after the beginning of haemodialysis treatment is a powerful predictor of cardiac event-free survival in patients with ESRD.

Keywords: cardiovascular mortality; coronary artery disease; end-stage renal disease; outcome; percutaneous transluminal coronary angioplasty; prospective cohort study; scintigraphic uptake



   Introduction
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 Abstract
 Introduction
 Subjects and methods
 Results
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Coronary events are the leading cause of mortality in patients with end-stage renal disease (ESRD), and often occur within the first year of haemodialysis [1,2]. Percutaneous coronary intervention in patients with ESRD is difficult because coronary lesions are calcified, multiple and complex. Furthermore, the restenosis rate of revascularized coronary vessels is higher in patients with ESRD than in patients without renal disease. However, the use of new devices, for example, coronary stenting and rotational atherectomy, has improved the long-term outcome in haemodialysis patients with coronary artery disease (CAD) [3,4]. Screening for CAD is not a standard practice in patients with ESRD, but is reserved for patients with clinical or electrocardiographic evidence of CAD. Coronary angiography is the most effective method for detecting CAD, but its cost is high and the risk of complications is significant [5]. Exercise testing, even when combined with myocardial perfusion imaging, is limited by the inability of patients with ESRD to perform sufficient exercise to exhaust myocardial reserve [6]. The frequent development of exercise-induced hypotension and difficulties in interpreting exercise electrocardiographic tracings in the presence of left ventricular hypertrophy reduce the value of this test. Pharmacologic stress myocardial perfusion imaging is a useful alternative for detecting myocardial ischaemia in patients unable to exercise, such as patients with ESRD. Dipyridamole or adenosine has been used as a stress agent very commonly in the US [7,8]. Although adenosine is considered safer than dipyridamole, it has been forbidden to use adenosine as a pharmacologic stress agent in Japan [9,10].

Myocardial concentrations of adenosine triphosphate (ATP) are high, and the half-life of ATP is <10 s [11]. Although the main effect of ATP depends on its oxidation to adenosine [11], direct stimulation of adenosine receptors by ATP cannot be excluded [12]. Less commonly, ATP has been used in pharmacologic stress testing to detect CAD [9,10,13], its accuracy being similar to that of dipyridamole [10]. At present, no studies of single photon emission computed tomography (SPECT) using ATP in patients with ESRD at the beginning of a haemodialysis session have been published.

The aim of this prospective study was to determine the prognostic value of stress thallium-201 SPECT using high-dose of ATP at the beginning of a haemodialysis session.



   Subjects and methods
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 Introduction
 Subjects and methods
 Results
 Discussion
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Patients
Fifty-one patients with ESRD admitted to our hospital for chronic haemodialysis between January 1, 2000, and May 31, 2002, were asked to participate in this study. Two patients required coronary angiography for a cardiac event within 1 month of starting haemodialysis. Consequently, 49 patients with ESRD were enrolled. Haematologic and biochemical examinations were performed just prior to the initial haemodialysis session. Resting electrocardiograms were performed immediately after admission in all patients. Echocardiograms just before discharge were performed using M-mode and two-dimensional ultrasonography with colour Doppler. The protocol recommended that echocardiograms be performed just after haemodialysis when the patient's symptoms were grade 1 according to New York Heart Association (NYHA) criteria, to avoid underestimating left ventricular function due to volume overload. Within 1 month of the beginning of haemodialysis treatment, pharmacologic stress thallium-201 SPECT using high-dose ATP was performed in all the patients. The study end-point was cardiac death, non-fatal myocardial infarction or clinical need for myocardial revascularization. All the patients completed 1-year of follow-up after stress thallium-201 SPECT, except the patients who died. During follow-up, patients were contacted periodically. In case of death, relatives were contacted.

Pharmacologic stress testing
Pharmacologic stress testing was performed with intravenous (i.v.) ATP (Adephos®, KOWA Inc., Nagoya) infusion after a 3-h fast. One vein in each arm was used to allow ATP and thallium-201 injection through different sites. An automatic infusion pump was used to infuse ATP (0.16 mg/kg/min) for 6 min. Electrocardiographic and haemodynamic monitoring was performed, and symptoms due to ATP infusion were recorded.

Thallium-201 SPECT study
Thallium-201 (111 MBq) was injected 5 min after the start of the ATP infusion. If chest pain, sinus bradycardia (<40 beats/min) or ST segment depression (>2 mm) occurred, the ATP infusion was stopped after the injection of thallium-201. Images of the stress cardiac scintigraphic study were acquired 5–10 min after the end of the infusion and 4-h later for the rest-redistribution. The studies consisted of 33 projections. Myocardial perfusion imaging was performed with a rotating three-headed gamma camera (MULTISPECT 3, SIEMENS Medical Solution USA Inc., IL) equipped with low-energy cardiofocal collimators and interfaced to computer (ICON, SIEMENS Medical Solution USA Inc., IL). Oblique tomograms reoriented in the short axis, horizontal axis and long axis were obtained. Presence of perfusion defects was determined blindly by two experts and classified reversible, fixed (non-reversible) or mixed (partially reversible). The myocardial washout rate of thallium-201 was defined as the per cent change in activity from the initial to the delayed images based on a bull's eye map. The washout rate was calculated using the equation: washout rate (%) = [(AB)/A] x 100, where A = average count/pixel in the left ventricle on the initial image and B = average count/pixel in the same region on the delayed image.

Cardiovascular history
A previous myocardial infarction was diagnosed when abnormal Q waves were present on the admission-resting electrocardiogram, or if the patient had a history of hospitalization for a myocardial infarction. Angina pectoris was diagnosed based on symptoms of chest pain. Congestive heart failure was diagnosed when dyspnoea was present and the patient required hospitalization. Stroke was diagnosed based on the presence of transient ischaemia attacks or anatomic evidence derived from CT. Peripheral artery disease was considered to be present when the patient had signs or symptoms of ischaemia.

Cardiac events
Myocardial infarction was diagnosed when new abnormal Q waves appeared on the electrocardiogram, the serum creatine phosphokinase-MB fraction concentration was elevated, or emergent percutaneous interventions and coronary angiography were performed. Sudden death was defined as a witnessed death that occurred within 1-h after the onset of acute symptoms, with no history of trauma. Myocardial revascularization was performed when progression of congestive heart failure or presence of unstable angina caused by CAD was confirmed by coronary angiography.

Statistical analysis
Quantitative variables with normal distribution are presented as mean±SD. The {chi}2 test for categorical variables and the unpaired t test for continuous variables were used to evaluate differences between measured values. Factors predictive of cardiac events were identified by Cox regression analysis. Factors with P<0.20 on univariate analysis were entered into the multivariate Cox regression model. A backward elimination procedure with P>0.05 to remove was performed to identify independent predictors of cardiac events in patients with ESRD. Survival analysis was performed by the Kaplan–Meier method and log-rank test. P values <0.05 were considered statistically significant. Statistical analysis was performed with commercially available software for Windows software (StatView 5.0, SAS Institute Inc., Cary, NC).



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 Subjects and methods
 Results
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Patient characteristics
There were 34 men and 15 women enrolled, ages 25–86 years. Haemodialysis was started 7–23 days prior to stress testing (14±6 days). The aetiology of renal failure was glomerular disease in 10, diabetes in 28 and hypertension in nine patients. Forty-five patients were considered hypertensive because they had overt hypertension classically defined before the beginning of a haemodialysis session or because they were receiving antihypertensive medication. Hypertension (systolic and diastolic blood pressure >160/90 mmHg) was treated during the follow-up period by angiotensin II receptor blockers in 21, angiotensin converting enzyme inhibitors in five, calcium channel blockers in 34 and beta-blockers in six patients. Six patients had a known CAD. Ten patients had a prior history of chest pain. Referral for typical angina occurred in four and atypical angina occurred in six patients. Nineteen patients had a prior history of congestive heart failure, and nine patients had a history of stroke or peripheral artery disease. The baseline characteristics of the study cohort are shown in Table 1.


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Table 1. Baseline characteristics of study patients

 

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Table 2. Baseline characteristics of study patients

 
Stress thallium-201 SPECT
Forty patients did not exhibit ATP-induced electrocardiographic change. Two patients had ST-segment depression, and three patients had sinus bradycardia. Five patients experienced side effects, including headache in four and chest pain in one patient. In three patients with sinus bradycardia and one patient with chest pain, the ATP infusion was stopped after the injection of thallium-201, and symptoms resolved within 1 min after the ATP infusion was stopped. Among the 49 patients studied, 24 patients (17 diabetics, 61% and seven non-diabetics, 33%) had perfusion defects; the defects were reversible in 13 (27%), mixed in nine (18%) and fixed in two patients (4%). The mean washout rate of thallium-201 was significantly lower in patients with perfusion defects (34±10%) than in patients without perfusion defects (44±10%, P<0.002). In the diabetic subgroup, there was a reversible perfusion defect in 10 (33%), mixed perfusion defect in six (20%) and fixed perfusion defect in one (3%) patient. The mean washout rate of thallium-201 was significantly lower in patients with a perfusion defect (31±8%) than in patients without a perfusion defect (43±10%, P<0.033).

Survival study
The mean follow-up was 9.6±3.7 months (range, 2–12 months; median, 12 months). The 1-year clinical outcomes are shown in Table 2. Twenty-two patients had coronary angiography because of myocardial infarction, progression of congestive heart failure or presence of unstable angina. Fifteen patients had a significantly stenotic coronary lesion. All patients who had a significantly stenotic coronary lesion underwent myocardial revascularization and were alive at the end of follow-up. The cumulative cardiac event rate within 1 year after the SPECT study was significantly higher in diabetic patients than in non-diabetic patients (47 vs 16%, P = 0.027). Two patients without coronary angiography died of cardiac causes. One diabetic patient without myocardial perfusion defects had a sudden death 6 months after the SPECT study. This patient was 49 years old, had a high left ventricular ejection fraction (71%), a low washout rate of thallium-201 (29%) and no history of cardiovascular disease. The other patient with a myocardial perfusion defect also suffered sudden death 8 months after the SPECT study. This patient was 72 years old, had a normal left ventricular ejection fraction (52%), a low washout rate of thallium-201 (30%), a history of congestive heart failure, a history of peripheral artery disease and no history of chest pain.

The cardiac event-free survival curves are shown in Figure 1. The 1-year cardiac event-free survival was 33 and 96% for patients with and without perfusion defects, respectively (P<0.0001, log-rank test). In the diabetic subgroup, the 1-year cardiac event-free survival rates were 18 and 92% for patients with and without perfusion defects, respectively (P<0.0001, log-rank test). Univariate Cox regression for the variables studied is shown in Table 3. The variables of diabetes, a history of congestive heart failure, a history of stroke or peripheral artery disease, serum creatinine concentration, serum C-reactive protein concentration, haemoglobin concentration and a perfusion defect were positively associated with 1-year cardiac events. Univariate Cox regression for the variables studied in the diabetic subgroup is presented in Table 4. Using stepwise multivariate Cox regression analysis, a myocardial perfusion defect proved the only independent predictor of a 1-year cardiac event both in overall patients and in diabetic patients with ESRD (Table 5).



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Fig. 1. Cardiac event-free survival curves in patients with and without myocardial perfusion defects. Patients with myocardial perfusion defects had a significantly worse cardiac event-free survival rate than patients with normal perfusion (P<0.0001, log-rank test).

 

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Table 3. Univariate Cox regression analysis in overall patients

 

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Table 4. Univariate Cox regression analysis in diabetes patient

 

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Table 5. Stepwise multivariate Cox regression analysis

 
CAD progression study
Using multivariate Cox regression analysis, diabetes (HR, 8.65; 95% CI, 1.41–52.68; P = 0.019) and a serum C-reactive protein concentration >=0.2 mg/dl (HR, 5.57; 95% CI, 1.08–28.84; P = 0.041) were positively associated with the progression of CAD after the SPECT study.



   Discussion
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 Abstract
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 Subjects and methods
 Results
 Discussion
 References
 
Although cardiac events are common within the first year of haemodialysis [1,2], screening for CAD by SPECT has not been performed. To our knowledge, this is the first prospective cohort study to show the ability of stress thallium-201 SPECT using high-dose ATP to identify patients with ESRD at risk for cardiac events. ATP stress myocardial perfusion SPECT was superior to clinical and historical data for predicting cardiac events.

Although the value of pharmacologic stress thallium-201 SPECT for diagnosing CAD has been established [912], the most important consideration is its prognostic value, and the ability to identify patients who need more aggressive treatment [10]. Myocardial perfusion studies in patients with ESRD were usually relying on exercise testing [14,15]. As many as 25–30% of patients with ESRD may not have been able to achieve maximal exercise stress, because of aging, sedentary life style, complication of CAD and/or peripheral artery disease [6]. In such patients, pharmacologic coronary vasodilation with dipyridamole or adenosine has been used successfully in combination with thallium-201 SPECT to identify CAD. Dipyridamole thallium-201 SPECT is generally considered safe. However, once side effects, such as bronchospasm and hypotension occur, they often result in hospitalization. Because the effect of dipyridamole 15–30 min when given intravenously, it is often necessary to administer i.v. aminophylline to reverse the side effects. Moreover, because the vasodilative effect of dipyridamole is an indirect result of raising endogenous adenosine levels, the magnitude of the effect varies among patients [16,17]. Although adenosine thallium-201 SPECT is considered safer than dipyridamole, it has been forbidden to use adenosine as a pharmacologic stress agent in Japan [9,10].

ATP is metabolized rapidly (<10 s). Although the vasodilative effect of ATP depends mostly on its metabolism to adenosine, direct simulation of adenosine receptor by ATP may also occur. ATP is an excellent anti-arrhythmic drug, widely used for the diagnosis and treatment of supraventricular tachycardia. Several investigators have reported that the diagnostic accuracy of stress thallium-201 SPECT with ATP is comparable with that of exercise or dipyridamole thallium-201 SPECT. The sensitivity, specificity and predictive accuracy among the three methods of stress thallium-201 SPECT are similar [9,10]. Side effects of ATP in our study were similar to those reported previously for ATP; this study supports the safety of stress testing with ATP [9,10,13]. No serious acute or persistent complications, such as severe hypotension or life-threatening arrhythmias, resulted from ATP administration.

The cardiac event-free survival rate was 96% in the small group of patients without myocardial perfusion defects during the first year of haemodialysis. Conversely, identification of perfusion defects is associated with an increased risk of cardiac events. Similar results have been found using other kinds of stress in different patient population [14,15,18]. We have noted previously that none of the diabetic patients without CAD, diagnosed by coronary angiography, died within 2 years after starting haemodialysis [19]. The one patient without a perfusion defect who died had a low washout rate of thallium-201 (29%). The data suggest that this patient had three-vessel coronary disease (false negative) or rapid progression of CAD after the SPECT study, and might have suffered a coronary event. Although the diagnostic accuracy of stress myocardial perfusion studies for CAD is lower than that of coronary angiography, the risk and the cost are also lower. Hence it is easier to justify pharmacologic stress testing as a screening procedure than it is coronary angiography. On the other hand, the cardiac events that did occur were the result of the progression of CAD, and 77% of diabetic and 43% of non-diabetic patients with myocardial perfusion defects had cardiac events within 1 year after the SPECT study. The speed of progression of CAD is rapid in patients with ESRD undergoing haemodialysis, and the progression of CAD is accelerated in patients with diabetes and an increased serum C-reactive protein concentration.

Recently, it has been reported that the incidence of atherosclerotic cardiovascular disease is high in patients with ESRD who have not yet begun haemodialysis [19,20]. Consequently the diagnosis of CAD is very important in determining the prognosis of patients with ESRD at the beginning of a haemodialysis session as well as in candidates for renal transplantation. The results of this study suggest that the most important risk factor for cardiac events in patients with ESRD is CAD at the beginning of haemodialysis, although diabetes and an increased C-reactive protein concentration may accelerate the progression of CAD after the start of chronic haemodialysis treatment. In patients with myocardial perfusion defects, the primary prophylaxis against the cardiac events should be anti-inflammatory treatment, and more aggressive interventional therapy in patients with progression of coronary lesions confirmed by coronary angiography. Special attention should be paid to diabetic patients with an increased C-reactive protein concentration who are at high risk for rapid progression of CAD, even in the absence of myocardial perfusion defects.

The present study has several limitations. First, multiple perfusion defects were not separated from single defects. The prognosis might have been different in patients with multiple perfusion defects if they had been studied as a separate subgroup. Secondly, the presence of perfusion defects might have been over represented in this study, because over 60% of the study patients had diabetes. Therefore, the quality of the data does not allow us to draw conclusions with the same confidence as would be derived from a large-scale risk matched trial. Finally, the availability and cost of using thallium-201 SPECT as a routine diagnosis method was not calculated. The actual cost-benefit ratio of thallium-201 SPECT for the patients with ESRD should be determined precisely.

In conclusion, pharmacologic stress thallium-201 myocardial perfusion SPECT using high-dose ATP at the beginning of a haemodialysis session predicts cardiac events in patients with ESRD. Normal myocardial perfusion is a powerful predictor for the 1-year cardiac event-free survival in patients with ESRD.

Conflict of interest statement. None declared.



   References
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

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Received for publication: 7. 7.03
Accepted in revised form: 20.11.03