Cardiac testing for coronary artery disease in potential kidney transplant recipients

Louis W Wang; Magid A Fahim; Andrew Hayen; Ruth L Mitchell; Laura Baines; Stephen Lord; Jonathan C Craig; Angela C Webster

doi:10.1002/14651858.CD008691.pub2

. 2011 Dec 7;2011(12):CD008691. doi: 10.1002/14651858.CD008691.pub2

Cardiac testing for coronary artery disease in potential kidney transplant recipients

Louis W Wang ^1,^2,^✉, Magid A Fahim ³, Andrew Hayen ⁴, Ruth L Mitchell ⁵, Laura Baines ⁶, Stephen Lord ⁷, Jonathan C Craig ^2,⁵, Angela C Webster ^2,^5,⁸

Editor: Cochrane Kidney and Transplant Group

PMCID: PMC7177243 PMID: 22161434

Abstract

Background

Patients with chronic kidney disease (CKD) are at increased risk of coronary artery disease (CAD) and adverse cardiac events. Screening for CAD is therefore an important part of preoperative evaluation for kidney transplant candidates. There is significant interest in the role of non‐invasive cardiac investigations and their ability to identify patients at high risk of CAD.

Objectives

We investigated the accuracy of non‐invasive cardiac screening tests compared with coronary angiography to detect CAD in patients who are potential kidney transplant recipients.

Search methods

MEDLINE and EMBASE searches (inception to November 2010) were performed to identify studies that assessed the diagnostic accuracy of non‐invasive screening tests, using coronary angiography as the reference standard. We also conducted citation tracking via Web of Science and handsearched reference lists of identified primary studies and review articles.

Selection criteria

We included in this review all diagnostic cross sectional, cohort and randomised studies of test accuracy that compared the results of any cardiac test with coronary angiography (the reference standard) relating to patients considered as potential candidates for kidney transplantation or kidney‐pancreas transplantation at the time diagnostic tests were performed.

Data collection and analysis

We used a hierarchical modelling strategy to produce summary receiver operating characteristic (SROC) curves, and pooled estimates of sensitivity and specificity. Sensitivity analyses to determine test accuracy were performed if only studies that had full verification or applied a threshold of ≥ 70% stenosis on coronary angiography for the diagnosis of significant CAD were included.

Main results

The following screening investigations included in the meta‐analysis were: dobutamine stress echocardiography (DSE) (13 studies), myocardial perfusion scintigraphy (MPS) (nine studies), echocardiography (three studies), exercise stress electrocardiography (two studies), resting electrocardiography (three studies), and one study each of electron beam computed tomography (EBCT), exercise ventriculography, carotid intimal media thickness (CIMT) and digital subtraction fluorography (DSF). Sufficient studies were present to allow hierarchical summary receiver operating characteristic (HSROC) analysis for DSE and MPS. When including all available studies, both DSE and MPS had moderate sensitivity and specificity in detecting coronary artery stenosis in patients who are kidney transplant candidates [DSE (13 studies) ‐ pooled sensitivity 0.79 (95% CI 0.67 to 0.88), pooled specificity 0.89 (95% CI 0.81 to 0.94); MPS (nine studies) ‐ pooled sensitivity 0.74 (95% CI 0.54 to 0.87), pooled specificity 0.70 (95% CI 0.51 to 0.84)]. When limiting to studies which defined coronary artery stenosis using a reference threshold of ≥ 70% stenosis on coronary angiography, there was little change in these pooled estimates of accuracy [DSE (9 studies) ‐ pooled sensitivity 0.76 (95% CI 0.60 to 0.87), specificity 0.88 (95% CI 0.78 to 0.94); MPS (7 studies) ‐ pooled sensitivity 0.67 (95% CI 0.48 to 0.82), pooled specificity 0.77 (95% CI 0.61 to 0.88)]. There was evidence that DSE had improved accuracy over MPS (P = 0.02) when all studies were included in the analysis, but this was not significant when we excluded studies which did not avoid partial verification or use a reference standard threshold of ≥70% stenosis (P = 0.09).

Authors' conclusions

DSE may perform better than MPS but additional studies directly comparing these cardiac screening tests are needed. Absence of significant CAD may not necessarily correlate with cardiac‐event free survival following transplantation. Further research should focus on assessing the ability of functional tests to predict postoperative outcome.

Plain language summary

[Summary title]

[Summary text]

Summary of findings

Summary of findings'. 'Summary of results.

Summary of results: Results of studies on cardiac testing in kidney transplant candidates
*Review question:* Comparison of non‐invasive cardiac screening tests with coronary angiography for the detection of significant CAD in potential kidney transplant recipients *Patient population:* Kidney transplant candidates undergoing pre‐transplant cardiac evaluation *Setting:* Investigations performed in hospital or in an outpatient setting *Geographical location:* Studies were conducted in USA (12 studies), Brazil (4 studies), India, (3 studies) the UK (3 studies), Australia (1 study), Canada (1 study), and Spain (1 study) *Index test* : Any non‐ or minimally invasive test used to assess risk of CAD. *Reference standard:* Coronary angiography *Included studies:* DSE (13 studies; 745 participants), MPS (9 studies; 582 participants), EST (2 studies; 129 participants), EBCT (1 study; 97 participants), DSF (1 study; 86 participants), exercise ventriculography (1 study; 35 participants), CIMT (1 study; 105 participants), resting wall motion abnormality on echocardiography (2 studies; 265 participants), left ventricular dysfunction on echocardiography (1 study; 52 participants), mitral annular calcification on echocardiography (1 study; 125 participants), resting ECG (3 studies; 263 participants).
Limitations
Only DSE and MPS were evaluated in detail, although these also had only a limited number of included comparisons with small sample sizes. No studies were found investigating cardiopulmonary exercise testing, CT coronary angiography, magnetic resonance angiography or cardiac magnetic resonance imaging. Fewer than five studies were found for each of EBCT, resting ECG, conventional echocardiography, exercise ventriculography, DSF and CIMT. Sparse directly comparative data also resulted in low power to detect important differences in accuracy between tests. Significant heterogeneity was present among studies investigating the same screening test. Although differences in study population characteristics (e.g. prevalence of chest pain) and test application (diagnostic test threshold, criteria for positive test, choice of stress agent and stress protocol, and operator variability) likely contributed to heterogeneity, we were hindered from estimating their contributions because of relatively sparse data, which resulted in low power. Partial verification, where not all patients who received screening tests also received coronary angiography, occurred in 5/25 comparisons. This may have affected estimates of sensitivity and specificity. Two different reference standard thresholds (≥ 70% stenosis or ≥ 50% stenosis) were used in the included studies, with most studies only using one reference standard threshold or the other. An overall analysis pooling the results of all studies regardless of threshold may introduce additional heterogeneity due to a threshold effect.
Results
Test	DSE	MPS
Number of studies [all studies]	13	9
Number of participants [all studies]	745	582
Pooled sensitivity (95% CI) [all studies]	0.79 (0.67 to 0.88)	0.74 (0.54 to 0.87)
Pooled specificity (95% CI) [all studies]	0.89 (0.81 to 0.94)	0.70 (0.51 to 0.84)
Number of studies [≥ 70% stenosis]	9	7
Number of participants [≥ 70% stenosis]	668	517
Pooled sensitivity (95% CI) [≥ 70% stenosis]	0.76 (0.60 to 0.87)	0.67 (0.48 to 0.82)
Pooled specificity (95% CI) [≥ 70% stenosis]	0.88 (0.78 to 0.94)	0.77 (0.61 to 0.88)
Number of false diagnoses of ≤ 70% coronary artery stenosis in a standard population of 100 patients (false negative rate)	24 (13 to 40) per 100	33 (18 to 52) per 100
Number of false diagnoses of ≥ 70% coronary artery stenosis in a standard population of 1000 patients (false positive rate)	12 (6 to 22) per 100	23 (12 to 39) per 100
Positive likelihood ratio [≥ 70% stenosis] (95% CI)	6.44 (3.03 to 13.70)	2.89 (1.39 to 5.99)
Negative likelihood ratio [≥ 70% stenosis] (95% CI)	0.26 (0.13 to 0.50)	0.43 (0.23 to 0.80)
Post test probability after positive screening test result for a patient with low risk (10% to 29% pre test probability) disease	42% to 72%	24% to 54%
Post test probability after positive screening test result for a patient with intermediate risk (30% to 59% pre test probability) disease	73% to 90%	55% to 81%
Post test probability after positive screening test result for a patient with high risk (60% to 90% pre test probability) disease	91% to 98%	81% to 96%
Post test probability after negative screening test result for a patient with low risk (10% to 29% pre test probability) disease	3% to 10%	5% to 15%
Post test probability after negative screening test result for a patient with intermediate risk (30% to 59% pre test probability) disease	10% to 27%	16% to 38%
Post test probability after negative screening test result for a patient with high risk (60% to 90% pre test probability) disease	28% to 70%	39% to 79%
Conclusions and comments
Both tests, especially DSE, have a role as triage tests for intermediate risk transplant candidates, with negative results precluding the need for further evaluation with coronary angiography, thereby avoiding unnecessary risk to patients and potentially reducing healthcare costs. Given the wide heterogeneity in the estimates for both DSE and MPS, there is still considerable uncertainty in the true post‐test probabilities of each test. Current evidence suggests that, where feasible, DSE should be used as the screening investigation of choice over MPS.
Applicability of tests in clinical practice
Both DSE and MPS have a role as triage tests for the intermediate risk transplant candidates, with negative results reducing the need for further evaluation with coronary angiography. In high risk patients, a positive non‐invasive DSE or MPS confirms the high risk of severe CAD, but a negative result does not conclusively rule out severe CAD. In these patients, one may consider proceeding immediately to coronary angiography and avoid using functional tests. The relatively low sensitivity and specificity of both DSE and MPS however means that they are not perfect triage tests and a significant number of patients will either have their significant CAD missed (false negatives) or be referred in vain for coronary angiography (false positive). Despite the shortcomings of the non‐invasive tests in their role as triage tests, the very select nature of the population and the unique challenges facing cardiac investigation in this population (particularly, the need to avoid complications arising from an invasive gold standard) and the lack of an alternate better performing test means that we are forced to accept an imperfect triage test. Functional testing may provide additional prognostic information, although an investigation into this was not included under the scope of this review.
Costs
None of the studies included a cost‐effectiveness evaluation. MPS is known to be more expensive than DSE, although both are less expensive than the reference standard, coronary angiography.

Test	Description	Advantages	Disadvantages	Type of result	Presence of cut‐off values
Screening tests
MPS Stress   Exercise   dipyridamole   dobutamine Radionucleotide   thallium‐201 or Tc‐99m sestamibi radionucleotide agents	This compares perfusion of myocardium at rest and after a ‘stress’ such as exercise or drugs (e.g. dipyridamole).     When coronary arteries are normal, ‘stress’ results in vasodilatation and increased coronary blood flow. However, diseased coronary arteries cannot dilate because they are already maximally dilated and there is no increase in blood flow after a stress. MPS reveals these areas as regions of decreased perfusion. A reversible perfusion defect is a sign of ischaemia. A fixed defect (when there is decreased perfusion before, during and after the stress) is an indicator of infarction. Pharmacological agents overcome limitations of exercise testing in patients with kidney disease	Non‐invasive Provides information regarding functional status of myocardium under stress conditions	Neither 100% sensitive nor specific Radiation dose Results subject to interpretation and reader bias False positives due to increase in attenuation artefacts caused by left ventricular hypertrophy False negatives due to balanced ischaemia (e.g. triple vessel disease) More expensive than exercise ECG	Dichotomous (i.e. stress test positive or stress test negative)	None. However, whether a stress test is interpreted as positive or negative depends largely on observer interpretation
DSE Stress   Exercise   dobutamine	Stress echocardiography compares the regional wall motion and thickness of myocardium both at rest and after stress. Regional systolic dysfunction is usually caused by CAD. Pharmacological stress agent overcomes limitations of exercise testing in patients with kidney disease	Non‐invasive No radiation dose Provides information regarding functional status of myocardium under stress conditions Provides assessment of ventricular size and function	Neither 100% sensitive nor specific Results subject to interpretation and reader bias Operator dependent Acoustic windows not possible in up to 20% of subjects Hypertensive response to stress agent possible Cardiomyopathies may also show regional variation in function	Dichotomous (i.e. stress test positive or stress test negative)	None. However, whether a stress test is interpreted as positive or negative depends largely on observer interpretation
Exercise ECG Bruce protocol stress ECG	Patient exercises on a treadmill while connected to an ECG. The level of exercise is increased in progressive stages. The patient's symptoms and blood pressure response are checked repeatedly. Ischaemic ECG changes or angina symptoms brought on by exercise are highly suggestive of underlying CAD	Non‐invasive Provides information regarding functional status of myocardium under stress conditions	Neither 100% sensitive nor specific Results subject to interpretation and reader bias Often limited by the inability of CKD patients to achieve an adequate peak exercise workload, development of exercise‐induced hypotension High proportion have abnormal baseline ECG (left ventricular hypertrophy)	Dichotomous (i.e. stress test positive or stress test negative)	No. However, whether a stress test is interpreted as positive or negative depends largely on observer interpretation
Coronary artery calcium score EBCT   Multidetector computed tomography	Cardiac calcium scoring is a non‐invasive test that uses computed tomography to detect the presence of calcium in plaque on the walls of the arteries of the heart (coronary arteries). A calcium score is then derived, calculated as a summation of all calcified lesions in the coronary arteries. The calcium score is then compared with a reference range appropriate to a patient's age and sex. High calcium scores are associated with higher risks of cardiovascular events	Non‐invasive	Neither 100% sensitive nor specific Radiation dose	Continuous	There is no uniformly agreed cut‐off value at which patients are considered at high risk of CAD. We planned to analyse results by combining data from studies which share identical cut‐off values
Echocardiography Trans‐thoracic   Trans‐oesophageal	An ultrasound of the heart that enables assessment of structure and function. Impairment in systolic function can result from pre‐existing CAD	Provides information regarding myocardial function and regional wall abnormalities, which may suggest pre‐existing ischaemia or MI Enables assessment of structure	Neither highly sensitive nor specific Does not provide any information of reversible ischaemia Results subject to interpretation and reader bias	Dichotomous (e.g. presence or absence of resting wall motion abnormality)	None
CT coronary angiography	Specialised form of CT that enables imaging of the heart and computerised reconstruction of coronary arteries, permitting assessment of the lumen and vessel walls	Non‐invasive Enables diagnosis of precise location and severity of each lesion as opposed to vascular territory affected, as is the case for most functional tests. Assesses not only the lumen of the vessel but also the wall. It can also demonstrate soft atheromatous plaques, which cannot be demonstrated on conventional coronary angiography	Radiation dose Contrast nephropathy Inability to provide opportunity for immediate intervention (as opposed to coronary angiography)	Dichotomous (i.e. presence or absence of significant CAD)	Yes (i.e. ≥ 50% stenosis or ≥ 70% stenosis) We planned to manage the issue of different cut points by involving an analysis that included: All studies regardless of threshold of CAD on coronary angiography (these will include both studies which have ≥ 50% stenosis and ≥ 70% stenosis Only studies which had ≥ 70% stenosis threshold
Cardiac magnetic resonance imaging	MRI of the heart that enables evaluation of its structure and function	Non‐invasive No radiation dose Enables assessment of structure of myocardium High spatial resolution means low inter‐observer variability	Neither highly sensitive nor specific	Dichotomous (e.g. presence or absence of left ventricular systolic dysfunction)	None
Resting ECG	Transthoracic interpretation of the electrical activity of the heart over time captured and externally recorded by skin electrodes	Provides information regarding the electrical function of the myocardium, which may suggest pre‐existing ischaemia, left ventricular hypertrophy or arrhythmias	Neither sensitive nor specific Does not provide any information of reversible ischaemia	Dichotomous (i.e. presence or absence of certain ECG features)	None
CIMT	Measurement of the thickness of artery walls, usually by external ultrasound, to detect both the presence and to track the progression of atherosclerotic disease in humans. Used as a surrogate marker for atherosclerosis	Non‐invasive	Neither highly sensitive nor specific Does not provide any information on cardiac function	Continuous	Yes. This will vary depending on the institution (e.g. 0.75 mm)
Cardiopulmonary exercise testing	Evaluates both cardiac and pulmonary function. Cardiac function is evaluated in terms of aerobic capacity and respiratory function. The subject is exercised on a bicycle ergometer or treadmill. The test enables calculation of maximal aerobic capacity and the point during exercise where anaerobic metabolism is used to supplement aerobic metabolism as a source of energy. These can be measured via gas exchange data	Non‐invasive measurement of ventricular function, respiratory function and cellular function via measurement of gas exchange, as well as detection of myocardial ischaemia Excellent method of evaluating fitness and operative fitness	Not commonly performed	Dichotomous (e.g. stress ECG positive or stress ECG negative; presence or absence of cardiac failure) and Continuous (e.g. measurement of the maximum aerobic capacity and anaerobic threshold)	Yes, although these will vary for different variables and for different institutions
DSF	Used to detect coronary artery calcification. Digital subtraction improves resolution of conventional fluoroscopic methods	Non‐invasive Non exercise	Not commonly used Radiation dose	Dichotomous (i.e. presence or absence of calcification)	None
Exercise radionucleotide ventriculography	Technique for a combined assessment of exercise capacity and an evaluation of ventricular size and performance		Not commonly used Radiation dose	Dichotomous (i.e. stress test positive or stress test negative)	None. However, whether a stress test is interpreted as positive or negative depends largely on observer interpretation
Reference standard
Coronary angiography	Coronary catheterisation is an invasive procedure to access the coronary circulation and blood filled chambers of the heart using a catheter. It can be performed for both diagnostic and interventional (treatment) purposes. It assesses the diameter of coronary artery lumens, heart chamber size and heart muscle contraction performance	Gold standard for detecting CAD. Enables diagnosis of precise location and severity of each lesion Intervention (PTCA) possible during procedure	High cost Lack of sensitivity to intramural coronary atherosclerosis Risk of complications Intravenous contrast media may worsen kidney function Little information on function Radiation dose Results subject to interpretation and reader bias, although to a lesser extent than functional tests	Dichotomous (i.e. presence or absence of significant CAD)	Yes (i.e. ≥ 50% stenosis or ≥ 70% stenosis). We managed the issue of different cut points by involving an analysis which included: All studies regardless of threshold of CAD on coronary angiography (these will include both studies which have ≥ 50% stenosis and ≥ 70% stenosis Only studies which had ≥ 70% stenosis threshold

Study	Country	Participants	Diabetic patients (%)	Angina (%)	Hypertensive (%)	Male (%)	Reference threshold (% stenosis)	TP	FP	FN	TN
*Dobutamine stress echocardiography (DSE)*
Bates 1996	USA	17	100	NA	98	64	50	9	1	1	6
Brennan 1997	USA	12	56	21	90	45	50	4	1	2	5
Cai 2010	USA	38	54	NA	86	64	70	15	2	8	13
De Lima 2003	Brazil	89	30	25	95	77	70	15	7	19	48
Ferreira 2007	Brazil	126	27	12	NA	69	70	24	14	10	78
Gang 2007	India	40	100	5	92	90	70	9	1	10	20
Garcia‐Canton 1998	Spain	27	NA	NA	NA	67	70	11	2	1	13
Herzog 1999	USA	50	82	16	94	60	70	12	8	4	26
Jassal 2007	Canada	18	38	NA	77	44	50	0	0	0	18
Reis 1995	USA	30	64	30	96	63	50	22	1	1	6
Sharma 2005	UK	125	39	42	91	64	70	32	5	4	84
Sharma 2009	UK	140	38	27	92	64	70	36	5	4	95
West 2000	USA	33	NA	NA	NA	NA	70	12	8	1	12
*Myocardial perfusion scintigraphy (MPS)*
Boudreau 1990	USA	80	100	12.5	NA	64	70	36	8	6	30
De Lima 2003	Brazil	65	30	25	95	77	70	8	10	15	32
Garcia‐Canton 1998	Spain	27	NA	NA	NA	67	70	11	3	1	12
Garg 2000	India	19	100	NA	100	88	50	9	4	2	4
Gowdak 2010	Brazil	219	100	NA	92	69	70	85	31	52	51
Krawczynska 1988	USA	46	NA	NA	NA	NA	50	20	18	0	8
Marwick 1990	USA	45	51	33	81	71	70	4	9	10	22
Vandenberg 1996	USA	41	100	0	NA	NA	75	10	6	6	19
Worthley 2003	Australia	40	78	18	98	48	70	13	3	2	22
*Stress electrocardiography (EST)*
Bennett 1978	USA	4	100	NA	100	36	70	3	1	0	0
Sharma 2005	UK	125	39	42	91	64	70	13	8	23	81
*Electron beam computed tomography (EBCT)*
Rosario 2010	Brazil	97	38	29	90	65	70	16	25	9	47
Sharples 2004	UK	18	NA	NA	NA	50	75	*	*	*	*
*Digital subtraction fluorography (DSF)*
Marwick 1989	USA	86	29	11	36	27	70	28	17	8	33
*Exercise ventriculography*
Vandenberg 1996	USA	35	100	0	NA	NA	75	7	7	7	14
*Carotid intimal media thickness (CIMT)*
Modi 2006	India	105	58	24	100	NA	97	38	14	4	49
*Echocardiography (resting wall motion abnormality)*
Sharma 2005	UK	125	39	42	91	64	70	11	4	25	85
Sharma 2009	UK	140	38	27	92	64	70	13	5	27	95
*Echocardiography (cardiomegaly or LV dysfunction)*
Garg 2000	India	19	100	NA	100	88	50	8	5	19	20
*Echocardiography (mitral annular calcification)*
Sharma 2005	UK	125	39	42	91	64	70	22	25	14	64
*Resting ECG (pathological Q waves, left ventricular hypertrophy, ST depression ≥ 1 mm, ST elevation ≥ 1 mm, T wave inversion or bundle branch block)*
Gang 2007	India	40	100	5	92	90	70	9	12	10	9
Garg 2000	India	98	100	NA	100	88	50	51	1	22	24
Sharma 2005	UK	125	39	42	91	64	70	27	14	9	75

Test	Studies (N)	Sensitivity (95% CI)	Specificity (95% CI)	Diagnostic odds ratio (95% CI)	AUC	P value for difference in accuracy*
*Overall results: including all studies*
MPS	9	0.74 (0.54 to 0.87)	0.70 (0.51 to 0.84)	6.69 (2.35 to 19.03)	0.78	0.02
DSE	13	0.79 (0.67 to 0.88)	0.89 (0.81 to 0.94)	29.98 (12.17 to 73.89)	0.91	0.02
*Only including studies where reference standard threshold ≥ 70% coronary artery stenosis on coronary angiography*
MPS	7	0.67 (0.48 to 0.82)	0.77 (0.61 to 0.88)	6.70 (1.84 to 24.41)	0.78	0.09
DSE	9	0.76 (0.60 to 0.87)	0.88 (0.78 to 0.94)	23.01 (8.08 to 65.51)	0.90	0.09
*Only including studies where partial verification was avoided*
MPS	8	0.68 (0.51 to 0.81)	0.75 (0.60 to 0.86)	6.45 (2.12 to 19.64)	0.78	0.03
DSE	9	0.80 (0.64 to 0.90)	0.89 (0.79 to 0.95)	34.28 (11.10 to 105.93)	0.92	0.03
*Only including studies which avoided partial verification and had reference standard threshold ≥ 70% coronary artery stenosis on coronary angiography*
MPS	7	0.67 (0.48 to 0.82)	0.77 (0.61 to 0.88)	6.70 (1.84 to 24.41)	0.78	0.09
DSE	8	0.78 (0.59 to 0.89)	0.88 (0.76 to 0.94)	25.22 (7.68 to 82.80)	0.90	0.09

Review	Population	DSE		MPS
Review	Population	Sensitivity (95% CI)	Specificity (95% CI)	Sensitivity (95% CI)	Specificity (95% CI)
Cochrane review	Kidney transplant candidates only	0.79 (0.67 to 0.88)	0.89 (0.81 to 0.94)	0.74 (0.54 to 0.87)	0.70 (0.51 to 0.84)
Fleischmann 1998	General population	0.85 (0.83 to 0.87)	0.77 (0.74 to 0.80)	0.87 (0.86 to 0.88)	0.64 (0.60 to 0.68)
Schinkel 2003	General population	0.80 (NS)	0.86 (NS)	0.84 (NS)	0.77 (NS)

Database	Search terms
MEDLINE	Kidney Transplantation/ Pancreas Transplantation/ (kidney and pancreas and (transplant$ or graft$)).tw. Kidney Failure/ Kidney Failure, Chronic/ (chronic kidney or chronic renal).tw. (endstage kidney or endstage renal).tw. (end stage kidney or end stage renal).tw. (ESRD or ESKD or ESRF or ESKF).tw. exp Renal Dialysis/ dialysis.tw. (hemodialysis or haemodialysis).tw. (hemodiafilt$ or haemodiafilt$).tw. (hemofilt$ or haemofilt$).tw. (PD or CAPD or CCPD or APD).tw. or/1‐15 Coronary Disease/ Coronary Artery Disease/ Coronary Stenosis/ (coronary arter$ and stenos$).tw. coronary stenos$.tw. coronary atheroscleros$.tw. coronary arterioscleros$.tw. (coronary adj5 disease).tw. CAD.tw. or/17‐25 and/16,26 exp Echocardiography/ echocardiogr$.tw. echo.tw. Dipyridamole/du [Diagnostic Use] Dobutamine/du [Diagnostic Use] Adenosine/du [Diagnostic Use] Imaging, Three Dimensional/ exp Tomography, Emission‐Computed/ exp Tomography, X‐ray Computed/ SPECT.tw. Thallium Radioisotopes/du [Diagnostic Use] Nucleosides/ Technetium Tc 99m Sestamibi/du [Diagnostic Use] ((sestamibi or cardiolite or dipyridamole or persantin) adj3 (scan$ or stud$)).tw. (thallium adj3 (scan$ or stud$)).tw. electron beam tomograph$.tw. EBT.tw. (comput$ adj2 tomograph$).tw. ct scan$.tw. cat scan$.tw. Magnetic Resonance Imaging/ Magnetic Resonance Angiography/ Diffusion Magnetic Resonance Imaging/ Echo‐Planar Imaging/ (echo‐planar or echoplanar).tw. Coronary Angiography/ Angiography/ MRI.tw. magnetic resonance.tw. MRA.tw. angiogr$.tw. coronary catheteri?ation.tw. (CA or CC).tw. (Fluoroscopy/ or fluoroscopy.tw.) and (Angiography, Digital Subtraction/ or Subtraction Technique/ or digital subtraction.tw.) exp Troponin/du [Diagnostic Use] calcium scor$.tw. Clinical Enzyme Tests/ cardiac enzyme$.tw. exp Perfusion Imaging/ perfusion imaging.tw. perfusion stud$.tw. perfusion scintigra$.tw. Exercise Test/ Radionuclide Ventriculography/ Physical Exertion/ stress test$.tw. exercise.tw. ventriculogra$.tw. treadmill.tw. bicycle.tw. Risk Assessment/ risk stratification.tw. risk algorithm.tw. exp Carotid Arteries/ and exp Ultrasonography/ exp Carotid Arteries/us (carotid adj2 (ultrasound or ultrasonogra$)).tw. Carotid Arteries/ and (Tunica Intima/ and Tunica Media/) (carotid media$ intima$ thickness or carotid intima$ media$ thickness).tw. or/28‐85 and/27,86
EMBASE	exp Kidney Transplantation/ Kidney Failure/ Chronic Kidney Failure/ Chronic Kidney Disease/ (kidney and pancreas and (transplant$ or graft$)).tw. (chronic kidney or chronic renal).tw. (endstage kidney or endstage renal).tw. (end stage kidney or end stage renal).tw. (ESRD or ESKD or ESRF or ESKF).tw. exp Renal Replacement Therapy/ dialysis.tw. (hemodialysis or haemodialysis).tw. (hemofilt$ or haemofilt$).tw. (hemodiafilt$ or haemodiafilt).tw. (PD or CAPD or CCPD or APD).tw. or/1‐15 Heart Disease/ Cardiovascular Disease/ Coronary Artery Disease/ Coronary Artery Atherosclerosis/ Coronary Artery Obstruction/ (coronary arter$ adj5 stenosis).tw. coronary atheroscleros$.tw. coronary arterioscleros$.tw. (coronary adj5 disease).tw. CAD.tw. or/17‐26 Angiography/ exp Cardiography/ exp Computer Assisted Tomography/ Arteriography/ exp Heart Function Test/ Xeroradiography/ Tomography/ exp Emission Tomography/ Magnetic Resonance Angiography/ Nuclear Magnetic Resonance Imaging/ Radiography/ Contrast Radiography/ Radioisotope Diagnosis/ (Fluoroscopy/ or fluoroscopy.tw.) and (Digital Subtraction Angiography/ or digital subtraction.tw.) exp Heart Scintiscanning/ Risk Assessment/ Carotid Artery/ and (Ultrasound/ or Echography/) Carotid Artery/ and ((Intima/ and Media/) or (Artery Intima/ and Artery Media/)) echocardiogr$.tw. echo.tw. (echo‐planar or echoplanar).tw. SPECT.tw. nucleoside$.tw. ((sestamibi or cardiolite or dipyridamole or persantin or thallium) adj3 (scan$ or stud$)).tw. electron beam tomograph$.tw. EBT.tw. (comput$ adj2 tomograph$).tw. ct scan$.tw. cat scan$.tw. MRA.tw. MRI.tw. magnetic resonance.tw. angiogr$.tw. coronary catheteri?ation.tw. ((dobutamine or adenosine) adj3 stress).tw. troponin.tw. calcium scor$.tw. cardiac enzyme$.tw. perfusion imaging.tw. perfusion stud$.tw. perfusion scintigra$.tw. stress test$.tw. exercise.tw. treadmill.tw. bicycle.tw. risk stratification.tw. risk algorithm.tw. (carotid adj2 (ultrasound or ultrasonogra$)).tw. (carotid adj2 (media$ intima$ thickness or intima$ media$ thickness)).tw. or/28‐76 and/16,27,77

Methodological variable	Operational definition/information required from each study
1. Representative spectrum (spectrum bias)	When included patients did not represent the intended targeted population, this may have led to an under‐ or overestimation of diagnostic accuracy depending on the difference between the targeted and included populations. The target spectrum in our review was patients with renal failure who were candidates for kidney transplantation. This was scored 'yes' if study participants included only patients with kidney disease who were considered to be candidates for kidney transplantation
2. Acceptable reference standard	An imperfect reference standard may have resulted in misclassification of disease positives and disease negatives. For the purpose of this review, studies had an acceptable reference standard if they used coronary angiography as the reference standard
3. Acceptable delay between tests (disease progression bias)	Disease may have progressed to a more advanced stage (i.e. greater degree of coronary artery stenosis) if a significant time interval between index and reference tests was observed, thereby leading to disease progression bias. This was scored as ‘yes’ if the delay between test was short (i.e. less than three months)
4. Partial verification avoided (verification bias)	Partial verification bias usually leads to an overestimation of sensitivity, although its effect on specificity varies. This item was scored ‘yes’ if all patients who received the index test were also evaluated by the reference standard
5. Differential verification avoided	This was scored ‘yes’ if no patients were verified with a second or third reference standard
6. Incorporation avoided (incorporation bias)	This bias usually leads to an overestimation of diagnostic test accuracy. Incorporation bias was deemed to have existed if the index test was incorporated in a composite reference standard. Studies were scored ‘yes’ if their classification of disease status did not directly involve the results of the index test
7. Reference standard results blinded (information bias)	When the reference standard was interpreted knowing the index test results, this may have led to the overestimation of diagnostic test accuracy. Studies were scored ‘yes’ if blinding of the reference standard was explicitly stated in the article or if this was acknowledged by authors in subsequent personal communication. Otherwise, the studies were marked ‘unclear’, unless blinding was explicitly stated to be absent
8. Index test results blinded (information bias)	When the index test results were interpreted without the knowledge of results of the reference standard, or with more information than in practice, this may have resulted in bias, usually leading to an overestimation of diagnostic accuracy. This item was scored ‘yes’ if blinding of the index test was explicitly stated in the article or if this was acknowledged by authors in subsequent personal communication. Otherwise, the studies were marked ‘unclear’, unless blinding was explicitly stated to be absent
9. Relevant clinical information (information bias)	The availability of clinical data during interpretation of test results may have affected estimates of test performance. This item was scored ‘yes’ if the data available during the study of diagnostic test accuracy was the same as that which would have been available in normal clinical practice
10. Uninterpretable results explained	This item was scored ‘yes’ if uninterpretable results were explained or if there were no uninterpretable results present. This item was scored 'no' if uninterpretable results were found but not explained
11. Withdrawals explained	Excluding patients from the study may have led to an overestimation of diagnostic accuracy. This item was scored ‘yes’ if withdrawals were explained or if there were no withdrawals from the study. This item was scored 'no' if there were withdrawals from the study, but these were unexplained

Test	No. of studies	No. of participants
1 DSE	13	745
2 MPS	9	582
3 EST	2	129
4 EBCT	1	97
5 DSF	1	86
6 EV	1	35
7 CIMT	1	105
8 Echo (RWMA)	2	265
9 Echo (LV)	1	52
10 Echo (MAC)	1	125
11 ECG	3	263

Clinical features and settings	Clinical features Adult patients who developed insulin dependent DM aged ≤ 25 years and underwent DSE before planned kidney or kidney‐pancreas transplantation between January 1989 and July 1993. Setting University Hospital, Indianapolis, Indiana, USA.
Participants	Number: 53 patients had preoperative screening; 17 received both DSE and coronary angiography DM: 100% Angina pectoris: Not reported Hypertension: 98% Sex: 64% male
Study design	Prospective, cohort study
Target condition and reference standard(s)	CAD on coronary angiography defined by ≥ 50% stenosis
Index and comparator tests	DSE Regional wall motion was graded as normal, hypokinetic, akinetic, or dyskinetic using a 16‐segment model at rest, low dose, peak dose, and recovery stages, and assigned a coronary vascular distribution. A study was considered abnormal if a wall motion abnormality involving ≥ 2 segments was present at rest or developed during stress.
Follow‐up	Patients were followed‐up for a mean of 498 ± 425 days (range 2 to 1269) after transplantation.
Notes
*Table of Methodological Quality*
Item	Authors' judgement	Description
Representative spectrum?   All tests	Yes	Adult patients with insulin‐dependent DM being considered for kidney and/or kidney‐pancreas transplantation.
Acceptable reference standard?   All tests	Yes	Coronary angiography with a reference standard threshold ≥ 50% stenosis.
Acceptable delay between tests?   All tests	No	18 patients underwent cardiac catheterisation within 101 ± 263 days (range = 200 days before to 557 days after) of DSE. Interval progression of CAD is possible.
Partial verification avoided?   All tests	No	18/53 patients underwent coronary angiography.
Differential verification avoided?   All tests	Yes	Disease status (CAD) diagnosed by coronary angiography.
Incorporation avoided?   All tests	Yes	Disease status (CAD) diagnosed by coronary angiography.
Reference standard results blinded?   All tests	Yes	All available catheterisation studies were interpreted by a blinded, experienced angiographer using digital callipers.
Index test results blinded?   All tests	Yes	All studies were interpreted by an experienced echocardiographer blinded to the clinical and stress electrocardiogram data.
Relevant clinical information?   All tests	Yes	Relevant clinical information was provided regarding the performance and analysis of both the index and reference tests.
Uninterpretable results reported?   All tests	Yes	No results were reported to be uninterpretable.
Withdrawals explained?   All tests	Yes	All patients missing from the final analysis were accounted for.

Clinical features and settings	Clinical features Patients with juvenile insulin‐dependent DM and ESKD who presented for kidney transplant cardiac evaluation. Eleven patients with evidence of arteriosclerotic heart disease gave their informed consent for coronary arteriogram and left ventricular angiogram. Seven patients had EST. Setting University of Oregon Health Sciences Center, Oregon, USA
Participants	Number: 4 participants DM: 100% Angina pectoris: percentage of patients with angina not reported Hypertension:, 100% Sex: 36% male
Study design	Cohort study
Target condition and reference standard(s)	Coronary artery stenosis measured by coronary angiography Absolute degree of stenosis recorded for each patient.
Index and comparator tests	EST
Follow‐up	30‐38 months, unless death occurred earlier.
Notes	Three of the seven patients had a non‐diagnostic stress test due to inadequate rate as a result of fatigue.
*Table of Methodological Quality*
Item	Authors' judgement	Description
Representative spectrum?   All tests	Yes	Patients with juvenile insulin‐dependent DM and ESKD who presented for kidney transplant cardiac evaluation.
Acceptable reference standard?   All tests	Yes	Coronary artery stenosis measured by coronary angiography. Absolute degree of stenosis recorded for each patient.
Acceptable delay between tests?   All tests	Unclear	Unclear, but likely to be only short delay between tests.
Partial verification avoided?   All tests	Yes	All patients received angiography.
Differential verification avoided?   All tests	Yes	This was not an issue in this study. Disease status (CAD) is diagnosed only through coronary angiography.
Incorporation avoided?   All tests	Yes	This was not an issue in this study. Disease status (CAD) is diagnosed only through coronary angiography.
Reference standard results blinded?   All tests	Unclear	Not reported.
Index test results blinded?   All tests	Unclear	Not reported.
Relevant clinical information?   All tests	Yes	Relevant clinical information was provided regarding the performance and analysis of both the index and reference tests.
Uninterpretable results reported?   All tests	Yes	No results were reported to be uninterpretable.
Withdrawals explained?   All tests	Yes	All patients missing from the final analysis were accounted for.

Clinical features and settings	Clinical features Patients with DM type 1 and ESKD who presented for kidney transplant evaluation Setting University of Minnesota Hospital and Clinics, Minnesota, USA
Participants	Number: 80 DM type 1: 100% Angina pectoris: 12.5% patients had history of myocardial infarction Hypertension: Not reported Sex: 64% male
Study design	Cross sectional study.
Target condition and reference standard(s)	Coronary artery stenosis measured by coronary angiography Coronary angiograms were analysed by a blinded observer who was unaware of thallium scan results or the patient’s history. Quantitative analysis sought to determine the percentage of cross sectional narrowing and absolute cross sectional diameter. The criterion for positive test results was ≥ 70% reduction in cross sectional area.
Index and comparator tests	Dipyridamole‐Tl‐201 scintigraphy MPS (40 oral, 40 IV dipyridamole) Scans interpreted by consensus of three experienced radiologists who were unaware of angiography results or patient history. Each view was subdivided into five segments, and the stress views (first set of images) examined for areas of reduced activity. Categorisation as 'indeterminate' was not permitted. Stress segments classified as abnormal were examined for definite, possible, or absent redistribution. Other categories were 'positive' and 'fixed defect'. Mixed defects were defined as areas of partial redistribution in a fixed defect or fixed defects in association with reversible defects. Quantitative analysis, including count profiles and washout rates, was also performed. However, only qualitative results were used to reach the final diagnosis, since normal quantitative values are unavailable for this test in this patient population.
Follow‐up	None.
Notes	Patients were reported as being followed‐up long‐term to assess the risk factors (including the thallium scan) for cardiac events after kidney transplantation, although no published data were available.
*Table of Methodological Quality*
Item	Authors' judgement	Description
Representative spectrum?   All tests	Yes	Patients with type 1 DM and ESKD who presented for kidney transplant evaluation.
Acceptable reference standard?   All tests	Yes	Coronary angiography with a reference standard threshold of ≥ 70% stenosis.
Acceptable delay between tests?   All tests	Unclear	Likely to be a short delay between tests.
Partial verification avoided?   All tests	Yes	All participants who underwent the index test also received the reference standard test.
Differential verification avoided?   All tests	Yes	Disease status (CAD) diagnosed by coronary angiography.
Incorporation avoided?   All tests	Yes	Disease status (CAD) diagnosed by coronary angiography.
Reference standard results blinded?   All tests	Yes	Coronary angiograms were analysed by a blinded observer (not the person who performed the angiography) who was unaware of the Tl‐201 scan results or the patient’s history.
Index test results blinded?   All tests	Yes	The scans were interpreted by consensus of three experienced radiologists who were unaware of the angiography results or patient history.
Relevant clinical information?   All tests	Yes	Relevant clinical information was provided regarding the performance and analysis of both the index and reference tests.
Uninterpretable results reported?   All tests	Yes	No results were reported to be uninterpretable.
Withdrawals explained?   All tests	Yes	No missing patients.

Clinical features and settings	Clinical features Patients with ESKD at risk of CAD who presented for kidney transplant cardiac evaluation Setting Washington University and Barnes‐Jewish Hospital, St. Louis, Missouri, USA
Participants	Number: 47 DM: 56% Hypertension: 90% Sex: 45% male Mean age: 51 years History of smoking: 61% Hypercholesterolaemia: 15% Coronary heart failure: 2% Clinical evidence CAD: 21%
Study design	Cohort study
Target condition and reference standard(s)	Coronary artery stenosis measured by coronary angiography The criterion for positive test results was ≥ 50% reduction in cross sectional area.
Index and comparator tests	DSE Two‐dimensional echocardiography as part of pretransplant evaluation. Graded infusions of dobutamine were administered (5 to 40 mg/kg/min) until the maximum predicted heart rate was achieved. If needed, IV atropine (0.4 to 2.0 mg) was given to increase heart rate to ˜85% of the maximum predicted heart rate. The test was terminated if patients developed: significant arrhythmia, severe hypertension or hypotension, or had new or worsening baseline segmental wall motion abnormalities in ≥ 2 major coronary perfusion regions. Segmental wall motion was scored according to American Society of Echocardiography recommendations, using lh‐segment model. Each segment was graded using a semi‐quantitative scoring system (normal or hyperdynamic (1); hypokinesis (2); akinesis (3); dyskinesis (4)). The wall motion score index was derived as an average of the 16 segments. All studies were reviewed independently by 2 experienced echocardiographers who were blinded to the clinical data.
Follow‐up	Follow‐up (range 3 to 64 months) data were obtained for all 47 participants.
Notes	Of the 47 patients who underwent DSE, all 5 patients who tested positive received coronary angiography. Seven other patients who had negative DSE received coronary angiography. The decision about providing coronary angiography for those who were index test negative was not made on grounds of clinical or high pre‐test suspicion (author correspondence).
*Table of Methodological Quality*
Item	Authors' judgement	Description
Representative spectrum?   All tests	Yes	Patients with ESKD at risk of CAD who presented for kidney transplant cardiac evaluation.
Acceptable reference standard?   All tests	Yes	Coronary angiography with a reference standard threshold of ≥ 50% stenosis.
Acceptable delay between tests?   All tests	Yes	Average time from DSE to coronary angiography < 9 months (author correspondence).
Partial verification avoided?   All tests	No	Of the 47 patients who underwent DSE, 5 who tested positive underwent coronary angiography, and 7 others who had negative DSE results also underwent coronary angiography. The reason that patients who were index test negative underwent coronary angiography was for other than clinical or high pre‐test suspicion (author correspondence)
Differential verification avoided?   All tests	Yes	Disease status (CAD) diagnosed by coronary angiography.
Incorporation avoided?   All tests	Yes	Disease status (CAD) diagnosed by coronary angiography.
Reference standard results blinded?   All tests	No	It is probable that the person who performed the coronary angiogram was aware of the DSE result. However, because later coronary angiograms were performed by an outside institution, this was not necessarily the case (author correspondence).
Index test results blinded?   All tests	Yes	All studies were reviewed independently by two experienced echocardiographers who were blinded to the clinical data.
Relevant clinical information?   All tests	Yes	Relevant clinical information was provided regarding the performance and analysis of both the index and reference tests.
Uninterpretable results reported?   All tests	Yes	No results were reported to be uninterpretable.
Withdrawals explained?   All tests	Yes	All patients missing from the final analysis were accounted for.

Clinical features and settings	Clinical features Patients presenting for pre‐transplant cardiac evaluation based on the presence of at least one of the following characteristics: age > 50 years, DM, angina, previous MI or stroke, left ventricular dysfunction, and extracardiac atherosclerosis. Subjects without these characteristics were not studied because they have a low frequency of coronary events. Setting Hospital das Clínicas, University of São Paulo Medical School, Brazil
Participants	Number: 150 (data from 24 participants excluded: lost to follow‐up (5); declined to continue (19)) DM: 30% Angina pectoris: 25% Hypertension: 95% Sex: 77% male
Study design	Cohort study.
Target condition and reference standard(s)	Coronary artery stenosis measured by coronary angiography The criterion for positive test results was ≥ 70% reduction in cross sectional area. Invasive and non‐invasive testing were analysed independently by 2 experts in the respective methods without previous knowledge of the experimental hypothesis. Disagreement was arbitrated by a third expert.
Index and comparator tests	DSE Stepwise infusion of dobutamine was started at 5 µg/kg/min and increased to 40 µg/kg/min in 3 minute stages. Inducible ischaemia was defined as hypokinesis or as accentuation of the degree of baseline hypokinesis during the infusion. The test was interrupted if SBP or DBP surpassed 220 mm Hg and 120 mm Hg, respectively, or when SBP fell below 90 mm Hg. Dipyridamole stress testing (single photon emission‐computed tomography with technecium‐99m methoxyisobutylisonitrite) Stress was induced by dipyridamole (0.5 mg/kg IV). Fixed perfusion defects were interpreted as evidence of fibrosis; transient hypoperfusion was interpreted as ischaemia.
Follow‐up	Five participants were lost to follow‐up. Minimum and mean follow‐up periods were 6 and 26 months, respectively. The outcome measure was cardiac events, predefined as sudden death, MI, life‐threatening arrhythmia, heart failure, pulmonary oedema, unstable angina, and myocardial revascularisation.
Notes
*Table of Methodological Quality*
Item	Authors' judgement	Description
Representative spectrum?   All tests	Yes	Kidney transplantation candidates as part of cardiac evaluation.
Acceptable reference standard?   All tests	Yes	Coronary angiography with a reference standard threshold of ≥ 70% stenosis.
Acceptable delay between tests?   All tests	Yes	Interval between tests was 2 to 6 weeks (author correspondence).
Partial verification avoided?   All tests	Yes	All participants who underwent an index test also received the reference standard test.
Differential verification avoided?   All tests	Yes	Disease status (CAD) diagnosed by coronary angiography.
Incorporation avoided?   All tests	Yes	Disease status (CAD) diagnosed by coronary angiography.
Reference standard results blinded?   All tests	No	No blinding for outcomes assessment.
Index test results blinded?   All tests	No	No blinding for outcomes assessment.
Relevant clinical information?   All tests	Yes	Relevant clinical information was provided regarding the performance and analysis of both the index and reference tests.
Uninterpretable results reported?   All tests	Yes	The number of tests that were submaximal were reported.
Withdrawals explained?   All tests	Yes	All patients missing from the final analysis were accounted for.

Clinical features and settings	Clinical features Kidney transplant candidates with diabetic kidney disease or other causes of CKD or ESKD undergoing cardiac evaluation. Examinations performed one day after haemodialysis. Setting Universidade Federal de São Paulo, Escola Paulista de Medicina, Hospital do Rim e Hipertensão e Hospital São Paulo, Brazil
Participants	Aged > 40 years, who presented with ≥ 2 risk factors Number: 126 participants DM: 27% Angina pectoris: 12% Hypertension: not reported Sex: 69% male Exclusion criteria Previous history of MI or surgical or percutaneous myocardial revascularization; unstable angina; decompensated CHF; significant aortic stenosis; pulmonary HTN; hypertrophic cardiomyopathy; inadequate echocardiographic window; atropine use restrictions (glaucoma and obstructive uropathy); irregular dialysis regimen.
Study design	Cross sectional study.
Target condition and reference standard(s)	Coronary artery stenosis measured by coronary angiography The criterion for positive test results was ≥70% reduction in cross‐sectional area.
Index and comparator tests	Dobutamine/atropine stress echocardiography Progressive doses of dobutamine 5, 10, 20, 30 and 40 μg/kg/min, with an increment every 3 minutes. In cases when the final objective of the evaluation had not been reached, 0.25 mg/min atropine was added simultaneously after the third minute of the infusion of 40 μg/kg/min of dobutamine, up to a total maximum cumulative dose of 1 mg. The test was considered diagnostic when either 85% of the maximum for age or echocardiographic signs of myocardial ischaemia was reached. The test was considered non‐diagnostic when there were inadequate images for the analysis (lack of definition on ≥ 2 myocardial segments); inability to reach target stress, and premature test withdrawal due to limiting side effects without attaining one of the test aims. Definitions guiding interpretation were: Normal result defined as uniform increase of systolic movement and thickening of the left ventricular wall and consequent reduction of its final systolic volume (global hyperdynamic response); a positive result for myocardial ischaemia was defined as a new alteration of the reversible segmental contractility or worsening of a pre‐existing segmental alteration, in ≥ 2 contiguous myocardial segments.
Follow‐up
Notes
*Table of Methodological Quality*
Item	Authors' judgement	Description
Representative spectrum?   All tests	Yes	Patients with ESKD who were kidney transplant candidates undergoing cardiac evaluation. Examinations performed one day after haemodialysis.
Acceptable reference standard?   All tests	Yes	Coronary angiography with a reference standard threshold of ≥ 70% stenosis.
Acceptable delay between tests?   All tests	Yes	Not longer than 2 months.
Partial verification avoided?   All tests	Yes	All participants who underwent an index test also received the reference standard test.
Differential verification avoided?   All tests	Yes	This was not an issue in this study. Disease status (CAD) is diagnosed only through coronary angiography.
Incorporation avoided?   All tests	Yes	This was not an issue in this study. Disease status (CAD) is diagnosed only through coronary angiography.
Reference standard results blinded?   All tests	Yes	The measurement bias was controlled through the “blind” interpretation of the test regarding the coronary angiography, which was considered the reference standard.
Index test results blinded?   All tests	Yes	The recorded images were later interpreted by two members who were blinded to the patients’ clinical data, as independent observers. The discordance was solved by consensus between the two observers.
Relevant clinical information?   All tests	Yes	Relevant clinical information was provided regarding the performance and analysis of both the index and reference tests.
Uninterpretable results reported?   All tests	Yes	Of 148 patients submitted to the test, 135 finished the protocol, which corresponds to a feasibility of 91%. The reasons that led to test interruption were: attaining 85% of maximum CF for age: 121 (81%); limiting side effects: 13 (9%); echocardiographic signs of ischaemia: 10 (7%) and end of the protocol: 4 (3%).
Withdrawals explained?   All tests	Yes	Thirteen patients presented an early withdrawal of the protocol due to limiting side effects: 12 (8.5%) due to hypertensive response and 1 (0.5%) due to severe angina.

Clinical features and settings	Clinical features Patients with DM and ESKD who presented for kidney transplant cardiac evaluation Setting Muljibhai Patel Urological Hospital, Gujarat, India
Participants	Number: 40 Type 2 DM: 100% ESKD: 100% Angina pectoris: 5% Hypertension: 92% Sex: 90% male
Study design	Cross sectional study.
Target condition and reference standard(s)	Coronary artery stenosis measured by coronary angiography Criterion for positive test results was ≥70% reduction in cross sectional area
Index and comparator tests	DSE DSE was performed by recording images in standard parasternal long‐ and short‐axis and apical 4 chamber and 2 chamber views at baseline, and during stepwise infusion of dobutamine in 3 minute stages at 5, 10, 20, 30 and 40 µg/kg/min. Atropine was administered as needed. DSE end points were target heart rate achieved ([220‐age]x0.85), maximum drug dose, intolerable angina, new inducible regional wall motion abnormalities in ≥ 2 coronary vascular territories, ventricular tachycardia, supraventricular tachycardia, hypotension and SBP > 240 mm Hg. Resting ECG Abnormal ECG findings included evidence of left ventricular hypertrophy by voltage criteria (8 patients), evidence of underlying ischaemia, or left bundle branch block.
Follow‐up	None
Notes	Patients underwent DSE followed by coronary angiography as a part of kidney transplant evaluation. Resting ECG was discounted from the analysis as "abnormal ECG". This was a heterogeneous concept that was suggestive of both ischaemic and non‐ischaemic (such as left ventricular hypertrophy) results. 12/40 patients (30%) had baseline ECG evidence of left ventricular hypertrophy by voltage criteria, 8 (20%) patients had evidence of underlying ischaemia; one patient (4%) had left bundle branch block. 19 patients had normal ECGs. 9/21 patients whose ECGs were abnormal had significant CAD on angiography.
*Table of Methodological Quality*
Item	Authors' judgement	Description
Representative spectrum?   All tests	Yes	Patients with DM and ESKD who presented for kidney transplant cardiac evaluation.
Acceptable reference standard?   All tests	Yes	Coronary angiography with a reference standard threshold of ≥ 70% stenosis.
Acceptable delay between tests?   All tests	Yes	DSE and coronary angiography were performed within the same week (author correspondence).
Partial verification avoided?   All tests	Yes	All participants who underwent an index test also received the reference standard test.
Differential verification avoided?   All tests	Yes	Disease status (CAD) diagnosed by coronary angiography.
Incorporation avoided?   All tests	Yes	Disease status (CAD) diagnosed by coronary angiography.
Reference standard results blinded?   All tests	No	The person who interpreted the coronary angiogram reports was not blinded to DSE results (author correspondence).
Index test results blinded?   All tests	Unclear	All coronary angiograms were performed after DSE, so index tests were likely to be performed without influence from the reference standard.
Relevant clinical information?   All tests	Yes	Relevant clinical information was provided regarding the performance and analysis of both the index and reference tests.
Uninterpretable results reported?   All tests	Yes	No results were reported to be uninterpretable.
Withdrawals explained?   All tests	Yes	No withdrawals reported.

Clinical features and settings	Clinical features Patients who presented for cardiac evaluation before kidney transplantation underwent DSE and MPS followed by coronary angiography Setting Hospital Universitario Insular de Gran Canaria, Spain
Participants	Number: 27 DM: percentage not reported ESKD: percentage not reported Angina pectoris: percentage not reported Hypertension: percentage not reported Sex: 67% male
Study design	Cross sectional study
Target condition and reference standard(s)	Coronary artery stenosis measured by coronary angiography Criterion for positive test results was ≥ 70% reduction in cross sectional area.
Index and comparator tests	DSE Stress 99M‐Technetium methoxyisobutylisonitrile SPECT
Follow‐up	None reported.
Notes	Conference presentation. Unpublished as a study. Additional information obtained from correspondence with authors.
*Table of Methodological Quality*
Item	Authors' judgement	Description
Representative spectrum?   All tests	Yes	Patients who presented for cardiac evaluation before kidney transplantation.
Acceptable reference standard?   All tests	Yes	Coronary angiography with a reference standard threshold of ≥ 70% stenosis.
Acceptable delay between tests?   All tests	Yes	All coronary angiography was performed from two weeks to three months after the other tests (author correspondence).
Partial verification avoided?   All tests	Yes	All participants who underwent the index test also had the reference standard test.
Differential verification avoided?   All tests	Yes	Disease status (CAD) diagnosed by coronary angiography.
Incorporation avoided?   All tests	Yes	Disease status (CAD) diagnosed by coronary angiography.
Reference standard results blinded?   All tests	Yes	Coronary angiography result was reported by a cardiology team member who was unaware of other test results (author correspondence).
Index test results blinded?   All tests	Yes	MIBI scan and DSE results were interpreted by clinical and technical experts without knowledge of the other. Both were conducted before coronary angiography.
Relevant clinical information?   All tests	Yes	Relevant clinical information was provided concerning the performance and analysis of both the index and reference tests (author correspondence).
Uninterpretable results reported?   All tests	Yes	There were no uninterpretable results.
Withdrawals explained?   All tests	Yes	There were no withdrawals reported.

Clinical features and settings	Clinical features Patients with DM who were candidates for kidney transplant Setting Sanjay Gandhi Post‐Graduate Institute of Medical Sciences, Lucknow, India
Participants	Number: 52 DM: 100% Angina pectoris: not reported Hypertension: 100% Sex: 88% male Age (Mean ± SD): 46 ± 6 years
Study design	Cohort study.
Target condition and reference standard(s)	Coronary artery stenosis measured by coronary angiography Criterion for positive test results was ≥ 50 reduction in cross sectional area. Each angiogram was independently reviewed by two experienced cardiologists who were blinded to the clinical data and uninvolved in patient management.
Index and comparator tests	DSTS Patients received400 mg oral dipyridamole and 1.5 mCi Tl‐201 injected IV one hour after DSTS. Studies were interpreted qualitatively and quantitatively. Planar thallium was performed in all cases. Normal test results were characterised by: the patient had no chest pain, no significant ST depression in the ECG during stress, and no significant perfusion defect. The test was considered positive if significant defects that were either fixed or reversible were revealed on delayed imaging, based on circumferential count profile analysis. Echocardiography Resting wall motion abnormality Resting ECG ECGs evaluated for evidence of MI, abnormal ST‐T changes, and left ventricular hypertrophy. Evidence of MI was regarded as positive if significant Q waves were present in more than one lead. ST‐T segment abnormality was noted as present if ST‐segment depression or elevation of at least 1 mm; or inverted T wave in any lead where the QRS complex had a net positive deflection were detected in the absence of bundle branch block and left ventricular hypertrophy.
Follow‐up	Survival data are available.
Notes	All patients underwent coronary angiography, echocardiography and resting ECG. 19 patients underwent dipyridamole MPS.
*Table of Methodological Quality*
Item	Authors' judgement	Description
Representative spectrum?   All tests	Yes	Patients with DM who were candidates for kidney transplant.
Acceptable reference standard?   All tests	Yes	Coronary angiography with a reference standard threshold of ≥ 50% stenosis.
Acceptable delay between tests?   All tests	Unclear	Likely to be short delay between tests.
Partial verification avoided?   All tests	Yes	All participants who underwent an index test received the reference standard test.
Differential verification avoided?   All tests	Yes	Disease status (CAD) diagnosed by coronary angiography.
Incorporation avoided?   All tests	Yes	Disease status (CAD) diagnosed by coronary angiography.
Reference standard results blinded?   All tests	Yes	Each angiogram was independently reviewed by two experienced cardiologists who were blinded to the clinical data and uninvolved in patient management.
Index test results blinded?   All tests	Yes	Studies were interpreted qualitatively and quantitatively.
Relevant clinical information?   All tests	Yes	Relevant clinical information was provided regarding the performance and analysis of both the index and reference tests.
Uninterpretable results reported?   All tests	Yes	No results were reported to be uninterpretable.
Withdrawals explained?   All tests	Yes	All patients missing from the final analysis were accounted for.

Clinical features and settings	Clinical features Patients with DM on dialysis who were candidates for kidney transplant Setting University of São Paulo Medical School, Brazil
Participants	Number: 219 DM: 100% Angina pectoris: not reported Hypertension: 92% Sex: 67% male Mean age: 57 years Mean duration on dialysis: 36 months
Study design	Cross sectional study.
Target condition and reference standard(s)	Coronary artery stenosis measured by coronary angiography Criterion for positive test results was ≥ 70% reduction in cross sectional area.
Index and comparator tests	SPECT+ Sestamibi cardiac scintigraphy Pharmacological stress induced by dipyridamole.
Follow‐up	Data not available.
Notes	Data obtained from poster presented at the European Society of Cardiology conference in 2010 http://spo.escardio.org/AbstractDetails.aspx?id=91377
*Table of Methodological Quality*
Item	Authors' judgement	Description
Representative spectrum?   All tests	Yes	Patients with DM who were candidates for kidney transplant.
Acceptable reference standard?   All tests	Yes	Coronary angiography with a reference standard threshold of ≥ 70% stenosis.
Acceptable delay between tests?   All tests	Unclear	Not reported.
Partial verification avoided?   All tests	Yes	All patients underwent coronary angiography.
Differential verification avoided?   All tests	Yes	Disease status (CAD) diagnosed by coronary angiography.
Incorporation avoided?   All tests	Yes	Disease status (CAD) diagnosed by coronary angiography.
Reference standard results blinded?   All tests	Unclear	Not reported.
Index test results blinded?   All tests	Unclear	Not reported.
Relevant clinical information?   All tests	Yes	Relevant clinical information was provided regarding the performance and analysis of both the index and reference tests.
Uninterpretable results reported?   All tests	Yes	No uninterpretable results present.
Withdrawals explained?   All tests	Yes	No withdrawals reported.

Clinical features and settings	Clinical features Patients referred for kidney transplantation evaluation from June 1992 to January 1995 ESKD from diabetic kidney disease or other causes unable to perform treadmill exercise ≥ 2 CAD risk factors: male; HTN; hypercholesterolaemia (total cholesterol level 240 mg/dL or low‐density lipoprotein cholesterol level 160 mg/dL); history of smoking; family history or any evidence suggestive of IHD (angina, effort dyspnoea, previous MI by history or ECG, or abnormal global or regional left ventricular function) Setting Hennepin County Medical Center, Minneapolis, Minnesota, USA
Participants	Patients were predominantly middle‐aged white men. Nearly all patients (92%) were undergoing chronic haemodialysis Number: 50 DM: 82% Angina pectoris: 16% Hypertension: 94% Sex: 60% male Exclusion criteria Significant aortic stenosis; unstable angina; inability to obtain informed consent; previous coronary angiography
Study design	Cohort study
Target condition and reference standard(s)	Coronary artery stenosis measured by coronary angiography Criterion for positive test result was ≥ 70% reduction in cross sectional area by quantitative coronary angiography.
Index and comparator tests	DSE End points for stopping drug infusion were: new inducible wall motion abnormalities involving ≥ 2 coronary artery vascular territories, intolerable patient discomfort, angina with ≥ 2 mm ST segment depression or elevation in a previously normal ECG lead, significant tachyarrhythmia (sustained supraventricular tachycardia or ≥ 3‐beat run of ventricular tachycardia), symptomatic severe hypotension, SBP ≥ 240 mm Hg or DBP ≥ 120 mm Hg, attaining target heart rate ([220 ‐ age] × 0.85), or reaching the maximum dose of dobutamine and atropine. DSE studies were analysed in digital format independently by three echocardiographers blinded to angiographic data. DSE study was defined as positive for inducible ischaemia when ≥ 1 normal segments developed absolute or relative hypokinesis with stress compared with other segments or an abnormal segment at rest had deterioration of regional systolic thickening with stress. DSE study result was normal if all segments were hyperdynamic with stress. If a resting baseline regional wall motion abnormality was unchanged with stress and all other segments became hyperdynamic, the DSE result was classified as a baseline regional wall motion abnormality with no inducible ischaemia.
Follow‐up	Patients were followed up for a mean of 22.5 ± 10.1 months.
Notes
*Table of Methodological Quality*
Item	Authors' judgement	Description
Representative spectrum?   All tests	Yes	Patients referred for kidney transplantation evaluation.
Acceptable reference standard?   All tests	Yes	Coronary angiography with a reference standard threshold of ≥ 70% stenosis.
Acceptable delay between tests?   All tests	Yes	47 patients had angiography within 2 weeks after DSE (median, 2 days; mean, 12.4 ± 41 days); three patients had angiographic studies at 69, 85, and 280 days after DSE (angiography was delayed wound infection (1 patient) and psychosocial reasons (2 patients).
Partial verification avoided?   All tests	Yes	All participants who underwent the index test received the reference standard test.
Differential verification avoided?   All tests	Yes	Disease status (CAD) diagnosed by coronary angiography.
Incorporation avoided?   All tests	Yes	Disease status (CAD) diagnosed by coronary angiography.
Reference standard results blinded?   All tests	Yes	All lesions occurring in the major coronary artery segments or their proximal branches were visually identified, and an initial qualitative assessment made by a skilled reader blinded to all clinical data.
Index test results blinded?   All tests	Yes	All DSE studies were analysed in digital format independently by three echocardiographers blinded to angiographic data.
Relevant clinical information?   All tests	Yes	Relevant clinical information was provided regarding the performance and analysis of both the index and reference tests.
Uninterpretable results reported?   All tests	Yes	No uninterpretable results were present.
Withdrawals explained?   All tests	Yes	55 eligible patients participated; 2 were excluded for unstable angina before scheduled testing; 3 underwent DSE and subsequently declined coronary angiography; 50 patients completed the research protocol. 39/50 patients qualified for DSE by the prespecified inclusion criterion of ESKD secondary to diabetic nephropathy (regardless of exercise capacity). The remaining 11 patients were unable to perform treadmill exercise because of peripheral vascular disease (4 patients), musculoskeletal disease (4 patients), lung disease (1 patient), and generalised fatigue (2 patients).

Clinical features and settings	Clinical features Between 2004 and 2006, 30 patients were prospectively evaluated who underwent both DSE and coronary angiography. This population included 12 patients (5 male, mean age 59 ± 13 years) referred to rule out CAD with normal kidney function (Cr < 2.0 mg/dL) and 18 patients (8 male, mean age 55 ± 12 years) with CKD (Cr > 2.0 mg/dL) on haemodialysis referred for pre‐renal transplant workup. Setting Boniface General Hospital, Manitoba, Canada
Participants	Number: 18 DM: 38% Angina pectoris: percentage not reported Hypertension: 77% Sex: 44% male
Study design	Cross sectional study
Target condition and reference standard(s)	Coronary artery stenosis measured by coronary angiography Criterion for positive test results was ≥ 50% reduction in cross sectional area.
Index and comparator tests	DSE Beta‐adrenergic blocking agents were withdrawn for 24 hours before the study. Dobutamine was infused at doses of 5, 10, 20, 30, and 40 mg/kg/min for 3 minutes each. Images were analysed using the standard16‐segment model
Follow‐up	None reported
Notes	Only data for the 18 patients referred for pre‐renal transplant workup were considered. Sufficient data in published report to create 2 x 2 table
*Table of Methodological Quality*
Item	Authors' judgement	Description
Representative spectrum?   All tests	Yes	Patients who presented for cardiac evaluation before kidney transplantation.
Acceptable reference standard?   All tests	Yes	Coronary angiography with a reference standard threshold of ≥ 50% stenosis.
Acceptable delay between tests?   All tests	Unclear	Likely to be short delay between tests.
Partial verification avoided?   All tests	Yes	All participants who underwent the index test also had the reference standard test.
Differential verification avoided?   All tests	Yes	Disease status (CAD) diagnosed by coronary angiography.
Incorporation avoided?   All tests	Yes	Disease status (CAD) diagnosed by coronary angiography.
Reference standard results blinded?   All tests	Unclear	Not reported.
Index test results blinded?   All tests	Unclear	Not reported.
Relevant clinical information?   All tests	Yes	Relevant clinical information was provided regarding the performance and analysis of both the index and reference tests.
Uninterpretable results reported?   All tests	Yes	No uninterpretable results were present.
Withdrawals explained?   All tests	Yes	No withdrawals were reported.

Clinical features and settings	Clinical features 305 patients with ESKD undergoing cardiac assessment prior to kidney transplant Setting Emory University School of Medicine, Georgia, USA
Participants	Number: 46 DM: percentage not reported Angina pectoris: percentage not reported Hypertension: percentage not reported Sex: not reported
Study design	Cohort study
Target condition and reference standard(s)	Coronary artery stenosis measured by coronary angiography Criterion for positive test results was ≥ 50% reduction in cross‐sectional area.
Index and comparator tests	Thalium‐201 Cardiac SPECT Stress was induced in 200 patients via exercise, 105 with dipyridamole. Reversible perfusion deficits constituted a positive test.
Follow‐up	Postoperative data available for outcomes of death and adverse cardiac events.
Notes	Only available in abstract form (presentation).
*Table of Methodological Quality*
Item	Authors' judgement	Description
Representative spectrum?   All tests	Yes	Prerenal transplant cardiac assessment. 305 ESKD patients waiting kidney transplantation.
Acceptable reference standard?   All tests	Yes	Coronary angiography with a reference standard threshold ≥ 50% stenosis.
Acceptable delay between tests?   All tests	Unclear	Likely to be short delay between tests.
Partial verification avoided?   All tests	No	38 patients received both coronary angiography and stress test.
Differential verification avoided?   All tests	Yes	Disease status (CAD) diagnosed by coronary angiography.
Incorporation avoided?   All tests	Yes	Disease status (CAD) diagnosed by coronary angiography.
Reference standard results blinded?   All tests	Unclear	Not stated in abstract.
Index test results blinded?   All tests	Unclear	Not stated in abstract.
Relevant clinical information?   All tests	Unclear	Insufficient clinical information provided about performance and analysis of the index and reference tests.
Uninterpretable results reported?   All tests	Yes	No results were reported to be uninterpretable.
Withdrawals explained?   All tests	Yes	All patients missing from the final analysis were accounted for.

PERMALINK

Cardiac testing for coronary artery disease in potential kidney transplant recipients

Louis W Wang

Magid A Fahim

Andrew Hayen

Ruth L Mitchell

Laura Baines

Stephen Lord

Jonathan C Craig

Angela C Webster

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Summary of findings

Summary of findings'. 'Summary of results.

Background

Target condition being diagnosed

Index test(s)

Rationale

Objectives

Secondary objectives

Investigation of sources of heterogeneity

Methods

Criteria for considering studies for this review

Types of studies

Participants

Inclusion criteria

Exclusion criteria

Index tests

1. Description of index tests.

Comparator tests

Target conditions

Reference standards

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

Data extraction and management

Assessment of methodological quality

Statistical analysis and data synthesis

2. Characteristics of included studies.

Investigations of heterogeneity

Sensitivity analyses

Results

Results of the search

1.

Methodological quality of included studies

2.

3.

Findings

4.

5.

Dobutamine stress echocardiography (DSE)

6.

7.

8.

Myocardial perfusion scintigraphy (MPS)

Other tests

Comparative analysis: DSE versus MPS

9.

3. Comparison of summary estimates of test performance for dobutamine stress echocardiography (DSE) and myocardial perfusion scintigraphy (MPS).

Subgroup analyses

Discussion

Summary of main results

Strengths and weaknesses of the review

Applicability of findings to the review question

4. Comparison of systematic reviews studying the test performance of myocardial perfusion scintigraphy and dobutamine stress echocardiography.

10.

Authors' conclusions

Implications for practice.

Implications for research.

Notes

Acknowledgements

Clinical features and settings	Clinical features ESKD patients undergoing coronary angiography as part of transplant workup over a 2 year period. Patients were selected on the basis of longstanding diabetes history of chest pain or previous MI, or age > 40. Setting Cleveland Clinic, Ohio, USA
Participants	Number: 86 DM: 29% Angina pectoris or IHD: 11% Hypertension: 36% Sex: 27% male
Study design	Cross sectional study.
Target condition and reference standard(s)	Coronary artery stenosis measured by coronary angiography CAD was defined as the presence of ≥ 1 coronary arteries with ≥ 50% diameter stenosis
Index and comparator tests	DSF Results were classified based on the presence or absence of calcification of the coronary arteries
Follow‐up	None reported.
Notes
*Table of Methodological Quality*
Item	Authors' judgement	Description
Representative spectrum?   All tests	Yes	ESKD patients undergoing cardiac evaluation as part of transplant workup.
Acceptable reference standard?   All tests	Yes	Coronary angiography with a reference standard threshold of ≥ 50% stenosis.
Acceptable delay between tests?   All tests	Yes	Tests performed at the same time.
Partial verification avoided?   All tests	Yes	All participants who underwent an index test received the reference standard test.
Differential verification avoided?   All tests	Yes	Disease status (CAD) diagnosed by coronary angiography.
Incorporation avoided?   All tests	Yes	Disease status (CAD) diagnosed by coronary angiography.
Reference standard results blinded?   All tests	Yes	Author correspondence.
Index test results blinded?   All tests	Yes	Author correspondence.
Relevant clinical information?   All tests	Yes	Relevant clinical information provided regarding performance and analysis of the index and reference tests.
Uninterpretable results reported?   All tests	Yes	No results were reported to be uninterpretable.
Withdrawals explained?   All tests	Yes	No withdrawals were reported.

Clinical features and settings	Clinical features ESKD patients with hypertension on maintenance dialysis undergoing pre‐transplant coronary angiography as per the institutional protocol if they were aged > 40 years to rule out CAD as part of transplant workup Setting Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India
Participants	Number: 105 DM: 61/105 (58%) Hypertension: all were hypertensive Sex: 102 (97.1%) male Age (mean ± SD): 51.6 ± 6.2 years (range 38 to 64 years)
Study design	Cross sectional study.
Target condition and reference standard(s)	Coronary artery stenosis measured by coronary angiography CAD defined as presence of ≥ 1 coronary arteries with ≥ 50% diameter stenosis
Index and comparator tests	CIMT measurement CIMT measurement was conducted on USG B mode 7.5 MHZ probe. At least three readings were taken, and the average of three readings was taken for evaluation. IMT on both sides was calculated and averaged. Plaques were defined as focal widening relative to the adjacent segments, with protrusion into the lumen, composed either of only calcified deposits or a combination of calcification and non‐calcified material. The site and extent of lesions were not quantified. Patients were further divided into two groups according to average CIMT (average IMT > 0.75 mm and those with IMT < 0.75 mm).
Follow‐up	None reported.
Notes
*Table of Methodological Quality*
Item	Authors' judgement	Description
Representative spectrum?   All tests	Yes	ESKD patients undergoing cardiac evaluation as part of transplant workup.
Acceptable reference standard?   All tests	Yes	Yes, coronary angiography with a reference standard threshold of ≥ 50% stenosis.
Acceptable delay between tests?   All tests	Unclear	Unclear, but likely to be only short delay between tests.
Partial verification avoided?   All tests	Yes	All participants who received an index test received the reference standard test.
Differential verification avoided?   All tests	Yes	This was not an issue in this study. Disease status (CAD) is diagnosed only through coronary angiography.
Incorporation avoided?   All tests	Yes	This was not an issue in this study. Disease status (CAD) is diagnosed only through coronary angiography.
Reference standard results blinded?   All tests	Yes	Reference standard performed before index test. Therefore it was not influenced by results of index test.
Index test results blinded?   All tests	Yes	An operator, who was blinded with respect to the results of the coronary angiography, measured CIMT in all patients prior to coronary angiography and recorded it on videotape. Two independent observers who were blinded to the result of coronary angiography, measured CIMT offline to validate its predictive accuracy as a noninvasive test in predicting the presence or absence of CAD.
Relevant clinical information?   All tests	Yes	Relevant clinical information was provided regarding the performance and analysis of both the index and reference tests.
Uninterpretable results reported?   All tests	Yes	No results were reported to be uninterpretable.
Withdrawals explained?   All tests	Yes	No withdrawals were present.

Clinical features and settings	Clinical features ESKD patients on dialysis undergoing cardiac evaluation (DSE) as part of transplant workup. Antihypertensive treatment and aggressive DM control were undertaken as clinically indicated Setting University of Michigan, Ann Arbor, Michigan, USA
Participants	Number: 97 patients underwent screening; only 30 patients received both DSE and coronary angiography DM: 64% Angina pectoris or history of IHD: 30% Hypertension: 96% Sex: 63% male
Study design	Cohort study.
Target condition and reference standard(s)	Coronary artery stenosis measured by coronary angiography CAD was defined as presence of ≥ 1 coronary arteries with ≥ 50% stenosis.
Index and comparator tests	DSE After completing a resting echocardiogram, stepwise infusion of dobutamine starting at 10 pg/kg/min, and increasing to 20 and a peak of 30 or 40 pg/kg/min in 3‐minute stages was initiated. All DSE studies were reviewed by experienced echocardiographers blinded to angiographic data and classified as: normal response: global increase in contractility, with an associated increase in ejection fraction, implying an absence of significant obstructive CAD (no regional wall motion abnormalities were seen at rest or during DSE). inducible ischaemia: wall motion abnormalities during DSE in 22 segments in regions that were normal at baseline, implying CAD without prior MI. fixed response: wall motion abnormality at baseline and no change during DSE implying prior MI without inducible ischaemia. mixed response: new and/or worsening wall motion abnormality in a patient with a wall motion abnormality at rest, implying prior MI with additional inducible ischaemia.
Follow‐up	12 ± 6 months.
Notes
*Table of Methodological Quality*
Item	Authors' judgement	Description
Representative spectrum?   All tests	Yes	ESKD patients undergoing cardiac evaluation as part of transplant workup.
Acceptable reference standard?   All tests	Yes	Coronary angiography with a reference standard threshold of ≥ 50% stenosis.
Acceptable delay between tests?   All tests	Yes	Within 4 months.
Partial verification avoided?   All tests	No	Coronary angiography was performed in 30/97 patients.
Differential verification avoided?   All tests	Yes	Disease status (CAD) diagnosed by coronary angiography.
Incorporation avoided?   All tests	Yes	Disease status (CAD) diagnosed by coronary angiography.
Reference standard results blinded?   All tests	Unclear	Not reported.
Index test results blinded?   All tests	Yes	All DSE studies were reviewed by experienced echocardiographers blinded to angiographic data.
Relevant clinical information?   All tests	Yes	Relevant clinical information was provided regarding the performance and analysis of both the index and reference tests.
Uninterpretable results reported?   All tests	Yes	No results were reported to be uninterpretable.
Withdrawals explained?   All tests	Yes	All patients missing from the final analysis were accounted for.

Clinical features and settings	Clinical features CKD patients in haemodialysis programs referred for kidney coronary angiography as part of a kidney transplant evaluation. The clinical indication for coronary angiography was based on the fact that the patients belonged to the group under high risk for CAD either due to symptoms and/or previous invasive exams that would lead to a suspicion of CVD. Setting Instituto do Coração (InCor) do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
Participants	Number: 97 DM: 38% Angina pectoris or IHD: 29% Hypertension: 90% Sex: 65% male
Study design	Cohort study.
Target condition and reference standard(s)	Coronary artery stenosis measured by coronary angiography CAD defined as presence of ≥ 1 coronary arteries with ≥ 70% diameter stenosis.
Index and comparator tests	Multi‐detector CT exams Performed in 16 and 64‐column detector‐row. Patients’ heart rates during examination = 61.1 ± 6.9 bpm. Patients with rates > 70 bpm on arrival for CT scan received IV beta‐blocker (metoprolol)to achieve 60 bpm, or the maximum dose (15 mg), since the protocol included associated coronary angiotomography acquisition. Calcium score obtained through prospective acquisition, and synchronised to ECG tracing. Images acquired were 3.0 mm thick, and view field was from 200 to 220 mm for chest axial images covering all cardiac area and allowing visualisation of coronary arteries and possible calcification on coronary artery topography. Images were acquired at a diastolic moment that was defined following patient’s heart rate.
Follow‐up	Follow‐up ongoing.
Notes
*Table of Methodological Quality*
Item	Authors' judgement	Description
Representative spectrum?   All tests	Yes	CKD patients already in a haemodialysis program and referred to be submitted to kidney transplant.
Acceptable reference standard?   All tests	Yes	Yes, coronary angiography with a reference standard threshold of ≥ 50 and 70% stenosis.
Acceptable delay between tests?   All tests	Yes	Time elapsed between Multi‐detector CT and coronary angiography was on average 99.03 days, SD 87.65 days, and median 79 days. Minimum interval was 2 days, and maximum interval was 380 days. Only 2 cases exceeded 1 year, and 16 cases had an interval over 6 months.
Partial verification avoided?   All tests	Yes	All participants who received an index test received the reference standard test.
Differential verification avoided?   All tests	Yes	This was not an issue in this study. Disease status (CAD) is diagnosed only through coronary angiography.
Incorporation avoided?   All tests	Yes	This was not an issue in this study. Disease status (CAD) is diagnosed only through coronary angiography.
Reference standard results blinded?   All tests	Yes	An observer experienced in QCA technique and who did not participate in the Multi‐detector CT analysis ‐ also blind and independent.
Index test results blinded?   All tests	Unclear	Not reported.
Relevant clinical information?   All tests	Yes	Relevant clinical information was provided regarding the performance and analysis of both the index and reference tests.
Uninterpretable results reported?   All tests	Yes	No results were reported to be uninterpretable.
Withdrawals explained?   All tests	Yes	No withdrawals were present.

Clinical features and settings	Clinical features ESKD patients referred for coronary angiography as part of cardiac work up before kidney transplantation Setting Two inner city renal units in Royal London and St Bartholomew’s Hospital, London, UK
Participants	Number: 18 DM: percentage not reported Angina pectoris: percentage not reported Hypertension: percentage not reported Sex: 50% male Man age: 53.9 years (range 31 to 73 years) Mean time on RRT: 27.4 months (range 4 to 111 months)
Study design	Cross sectional study
Target condition and reference standard(s)	Coronary artery stenosis measured by coronary angiography CAD defined as presence of ≥ 1 coronary arteries with at least 50% stenosis.
Index and comparator tests	EBCT Images were performed with a 100‐ms scanning time and a single slice thickness of 3 mm. 36 to 40 tomographic slices were obtained for each subject during 2 breath‐holding sessions. The degree of coronary artery calcification was calculated by multiplying the area of each calcified lesion by a weighting factor corresponding to the peak pixel intensity for each lesion to yield a lesion‐specific calcification score. The proximal segments of the left main stem, left anterior descending, left circumflex and right coronary arteries were examined.
Follow‐up	None reported.
Notes	Results reported per vessel, not per patient. Insufficient data to construct meaningful 2 x 2 table. Therefore, study did not contribute data to the meta‐analysis.
*Table of Methodological Quality*
Item	Authors' judgement	Description
Representative spectrum?   All tests	Yes	ESKD patients assessed for CAD before kidney transplant.
Acceptable reference standard?   All tests	Yes	Coronary angiography with a reference standard threshold of ≥ 75% stenosis.
Acceptable delay between tests?   All tests	Unclear	Likely to be short delay between tests.
Partial verification avoided?   All tests	Yes	All participants who underwent the index test received the reference standard test.
Differential verification avoided?   All tests	Yes	Disease status (CAD) diagnosed by coronary angiography.
Incorporation avoided?   All tests	Yes	Disease status (CAD) diagnosed by coronary angiography.
Reference standard results blinded?   All tests	Yes	Analysis of the coronary angiograms was performed using a digital analysis system operated by a cardiologist blinded to the calcification score.
Index test results blinded?   All tests	Yes	The acquired images were scored with the use of Imatron software by a single radiologist blinded to the clinical or angiographic history of the patient.
Relevant clinical information?   All tests	Yes	Relevant clinical information was provided regarding the performance and analysis of both the index and reference tests.
Uninterpretable results reported?   All tests	Yes	There were no uninterpretable results.
Withdrawals explained?   All tests	Yes	There were no withdrawals.

Clinical features and settings	Clinical features Patients with kidney disease and DM referred for kidney and/or pancreas transplantation from 1988 to 1993 undergoing cardiac evaluation as part of transplant workup with no history of angina, MI, coronary artery bypass surgery, or percutaneous transluminal coronary angioplasty; pharmacologic stress thallium scintigraphy and/or exercise radionuclide ventriculography performed as part of the evaluation; and coronary artery angiography performed within 6 months after the radionuclide evaluation (and no cardiac symptoms in the interim period). Setting Cardiovascular Center, University of Iowa College of Medicine, Iowa, USA
Participants	Number: 47 DM: 100% Angina pectoris or IHD: Nil Hypertension: 74%. 35/74 (74%) Patients were taking antihypertensive medications, including beta blockers and calcium channel blockers; medications were continued during stress testing Sex: not reported
Study design	Cohort study
Target condition and reference standard(s)	Coronary artery stenosis measured by coronary angiography CAD defined as presence of ≥ 1 coronary arteries with ≥ 75% diameter stenosis. Separate data available for 50% stenosis
Index and comparator tests	Pharmacologic stress thallium scintigraphy IV dipyridamole was infused at a rate of 0.142 mg/kg per min for 4 min. IV adenosine was infused at a rate of 0.14 mg/kg per min for 6 min. Thallium‐201 (3 mCi) was injected IV 5 min after the completion of the dipyridamole infusion or 4 min after the beginning of the adenosine infusion. Imaging was performed within 10 min with a gamma‐camera. Planar images in anterior and lateral projections were obtained and were followed immediately by single‐photon emission CT imaging. Images were interpreted by consensus of two experienced radiologists who were unaware of the angiography results. Test results were considered abnormal if either a fixed or a reversible defect was present. Exercise radionuclide ventriculography Radionuclide ventriculography was performed in 40 patients using a modified in vivo red blood cell‐labelling technique with an initial IV injection of 5.1 mg of stannous pyrophosphate, followed by 25 to 30 mCi of technetium‐99m pertechnetate. Patients performed semi supine exercise with a bicycle ergometer table during continuous 12‐lead ECG monitoring. Exercise was begun at a pedal speed of 50 rpm and a work load of about 50 watts, which was increased by 10 watts every 30 sec to a symptom‐limited maximum. Heart rate and blood pressure were recorded at each exercise level. Images were obtained in the left anterior oblique projection at peak exercise and ejection fraction was calculated from this image. Exercise was considered adequate if the peak rate pressure product was > 20,000 or if the rate pressure product at least doubled from baseline to peak exercise. A test result was considered abnormal if any of the following were present: resting ejection fraction of < 50% failure to increase ejection fraction by at least 5 percentage points (in female subjects and in those with a resting ejection fraction of > 60%, the failure to increase ejection fraction was not considered abnormal); or a new wall motion abnormality with exercise
Follow‐up	The mean time from thallium scintigraphy to the latest follow‐up visit was 35 ± 19 months.
Notes
*Table of Methodological Quality*
Item	Authors' judgement	Description
Representative spectrum?   All tests	Yes	Renal failure patients undergoing cardiac evaluation as part of transplant workup.
Acceptable reference standard?   All tests	Yes	Yes, coronary angiography with a reference standard threshold of ≥75% stenosis.
Acceptable delay between tests?   All tests	Yes	Angiography was performed 55 ± 42 days after thallium scintigraphy in 42 patients and 50 ± 45 days after exercise radionuclide ventriculography in 40 patients.
Partial verification avoided?   All tests	Yes	All participants who received an index test received the reference standard test.
Differential verification avoided?   All tests	Yes	This was not an issue in this study. Disease status (CAD) is diagnosed only through coronary angiography.
Incorporation avoided?   All tests	Yes	This was not an issue in this study. Disease status (CAD) is diagnosed only through coronary angiography.
Reference standard results blinded?   All tests	Yes	Measurements were made by a single observer without knowledge of the results of the imaging tests.
Index test results blinded?   All tests	Yes	Images were interpreted by the consensus of two experienced radiologists who were unaware of the angiography results.
Relevant clinical information?   All tests	Yes	Relevant clinical information was provided regarding the performance and analysis of both the index and reference tests.
Uninterpretable results reported?   All tests	Yes	Yes. One MPS was technically suboptimal and was therefore not included in the analysis. Exercise ventriculography was suboptimal in five patients and they were not included in the analysis.
Withdrawals explained?   All tests	Yes	All patients missing from the final analysis were accounted for.

Clinical features and settings	Clinical features Dialysis‐dependent renal transplant candidates evaluated between 1 January l993 and 1 March l995 were screened for cardiac high‐risk factors (identified as those with diabetes mellitus, previous MI, age 50 years or more cerebral and/or peripheral vascular disease, CHF, class I or II angina (Canadian Cardiovascular Society classification), and dialysis dependency of more than 5 years). Setting Geisinger Medical Center, Danville, Pennsylvannia, USA
Participants	Number: 33 DM: percentage not reported Angina pectoris or IHD: percentage not reported Hypertension: percentage not reported Sex: not reported
Study design	Cohort study
Target condition and reference standard(s)	Coronary artery stenosis measured by coronary angiography CAD was defined as the presence of one or more coronary arteries with 70% or greater diameter stenosis, or greater than 50% in left main coronary artery.
Index and comparator tests	DSE DSE was performed the day after dialysis to avoid hypertensive blood pressure response from volume overload. A standardised DSE protocol was used. DSE findings were graded as negative if normal wall motion was present and positive when: CAD: fixed, inducible, or mixed segmental wall motion abnormalities Cardiomyopathy: diffuse wall motion abnormalities or Primary valvular heart disease: severe aortic stenosis, aortic insufficiency, mitral stenosis, or mitral regurgitation secondary to primary leaflet abnormalities were present
Follow‐up	Patients were followed up for an unspecified time.
Notes
*Table of Methodological Quality*
Item	Authors' judgement	Description
Representative spectrum?   All tests	Yes	ESKD patients undergoing cardiac evaluation as part of transplant workup.
Acceptable reference standard?   All tests	Yes	Coronary artery stenosis measured by coronary angiography. CAD defined as the presence of ≥ 1 coronary arteries with ≥ 70% diameter stenosis, or > 50% in left main coronary artery.
Acceptable delay between tests?   All tests	Unclear	Likely to be only delay between tests.
Partial verification avoided?   All tests	Yes	All participants who underwent the index test received the reference standard test.
Differential verification avoided?   All tests	Yes	Disease status (CAD) diagnosed by coronary angiography.
Incorporation avoided?   All tests	Yes	Disease status (CAD) diagnosed by coronary angiography.
Reference standard results blinded?   All tests	Unclear	Not reported.
Index test results blinded?   All tests	Unclear	Not reported.
Relevant clinical information?   All tests	Yes	Relevant clinical information was provided regarding the performance and analysis of the index and reference tests.
Uninterpretable results reported?   All tests	Yes	There were no uninterpretable results.
Withdrawals explained?   All tests	Yes	Nine patients were excluded because of prior coronary angiography (5), class III ± IV angina (3), and refusal to participate in the study (1).

Study	Reason for exclusion
Ali 2004	Coronary angiography not routinely performed on patients in study.
Arantes 2010	Prognostic study; not enough data available to allow for diagnostic accuracy comparison with coronary angiography.
Braun 1984	No index tests for comparison.
Brown 1989	Prognostic study; not enough data available to allow for diagnostic accuracy comparison with coronary angiography.
Caglar 2006	Patient population not consisting of patients who are potential transplant recipients; coronary angiography only provided to patients who tested positive to other tests.
Camp 1990	Coronary angiography not used as reference standard.
Cortigiani 2005	Coronary angiography not used as reference standard.
Cottier 1990	Coronary angiography not routinely performed on patients in study.
Cross 1996	Prognostic study; not enough data available to allow for diagnostic accuracy comparison with coronary angiography.
Dahan 1995	Patient population not entirely consisting of patients who are potential transplant recipients. Separate data for potential transplant recipients not available.
Dahan 1998	Patient population not entirely consisting of patients who are potential transplant recipients. Separate data for potential transplant recipients not available.
Dahan 2002	Patient population not entirely consisting of patients who are potential transplant recipients. Separate data for potential transplant recipients not available.
De Vriese 2009	Patient population not entirely consisting of patients who are potential transplant recipients. Roughly 1/3 of the patients that were included in the study were being evaluated for kidney transplantation. The others consented to have the evaluation as a screening test, because the authors explained to them that the majority of patients with CAD on dialysis are asymptomatic (author communication). Separate data for potential transplant recipients not available.
Derfler 1991	Coronary angiography not used as reference standard.
Dussol 2004	Coronary angiography not routinely performed on patients in study, only performed on patients who were index test positive.
Eschertzhuber 2005	Coronary angiography not routinely performed on patients in study.
Feola 2002	Coronary angiography not used as reference standard.
Fossati 2004	Data insufficient to construct appropriate 2 x 2 table.
Fujimoto 2006	This was a study of diagnostic accuracy but the patient population did not consist entirely of patients who are potential transplant recipients. Separate data on patients who were potential transplant recipients not available.
Fukui 2005	This was a study of diagnostic accuracy but the patient population did not consist entirely of patients who are potential transplant recipients. Separate data on patients who were potential transplant recipients not available.
Fuster 2000	Coronary angiography not routinely performed on patients in study, only performed on patients who were index test positive.
Holley 1991	Coronary angiography not routinely performed on patients in study; data insufficient to construct appropriate 2 x 2 table.
Iqbal 1991	Coronary angiography not used as reference standard.
Jeloka 2007	Coronary angiography not used as reference standard.
Krotin 2007	Coronary angiography not used as reference standard.
Langford 1997	Coronary angiography not used as reference standard.
Le 1994	Prognostic study; not enough data available to allow for diagnostic accuracy comparison with coronary angiography.
Leonardi 2009	Single centre case experience; not a study of diagnostic accuracy.
Lewis 2002	Prognostic study; not enough data available to allow for diagnostic accuracy comparison with coronary angiography.
Lin 2001	Coronary angiography not used as reference standard.
Ma 2006	Coronary angiography only used in those with high risk scores.
Manske 1997	Data insufficient to construct appropriate 2 x 2 table.
Mao 2010	Coronary angiography not used as reference standard.
Mistry 1998	Coronary angiography not used as reference standard.
Morrow 1983	Coronary angiography not used as reference standard.
Nguyen 2007	Coronary angiography not used as reference standard.
Nishimura 2004	This was a study of diagnostic accuracy but the patient population did not consist entirely of patients who are potential transplant recipients. Separate data on patients who were potential transplant recipients not available.
Ohtake 2005	This was a study of diagnostic accuracy but the patient population did not consist entirely of patients who are potential transplant recipients. Separate data on patients who were potential transplant recipients not available.
Oliveira 2005	Only coronary angiography studied. No other index tests present.
Patel 2003	Coronary angiography not used as reference standard.
Patel 2008	Coronary angiography not routinely performed on patients in study.
Philipson 1986	Reference standard differentially applied to different treatment groups; unable to construct meaningful 2 x 2 table.
Porter 2003	Coronary angiography not used as reference standard.
Rakhit 2006	Coronary angiography not used as reference standard.
Robinson 2007	This was a study of diagnostic accuracy but the patient population did not consist entirely of patients who are potential transplant recipients. Separate data on patients who were potential transplant recipients not available.
Russell 1993	Prognostic study; not enough data available to enable diagnostic accuracy comparison with coronary angiography.
Schmidt 2001	Patient population not exclusively consisting of patients who are potential transplant recipients; patients were either those who were on long‐term RRT, or who had undergone successful renal transplantation. Separate data on patients who were potential transplant recipients not available.
Sharma 2007	Coronary angiography not used as reference standard.
Tita 2008	Coronary angiography not used as reference standard.
Trochu 1991	Coronary angiography not used as reference standard.
Venkataraman 2008	Coronary angiography not used as reference standard.
Weinrauch 1978	Only coronary angiography studied. No index tests for comparison.
Weinrauch 1992	Coronary angiography not used as reference standard.
Witczak 2006	Only coronary angiography studied. No index tests for comparison.
Wong 2008	Coronary angiography not used as reference standard.