Review article: Coronary artery stenoses: Detection and revascularization in renal disease
Dr Helen L Pilmore, Auckland Hospital, Department of Renal Medicine, Park Road Auckland, Auckland 1000, New Zealand. Email: firstname.lastname@example.org
Cardiovascular events are markedly elevated in those with all degrees of renal impairment compared to the general population. There are well established guidelines in the general population for the management of coronary artery disease, however, similar guidelines have not been established in the renal population. This review examines the current published work on the detection of coronary artery stenoses in addition to summarizing the outcomes of revascularization in patients with kidney disease. Testing for coronary artery disease in the renal population most commonly occurs in dialysis patients as part of their assessment for renal transplantation. While a positive myocardial stress test for the detection of significant coronary artery stenoses is associated with an increased risk of cardiac events, there is no clear information currently showing that cardiovascular testing itself reduces the rate of adverse cardiac events after transplantation. Revascularization of coronary artery stenoses is associated with higher morbidity and mortality in all groups with kidney disease than in the general population, with the exception of renal transplant recipients where the mortality is likely to be similar to that of the general population. There appears to be a benefit in coronary artery bypass surgery compared to percutaneous intervention in those on dialysis and after renal transplant. Currently, there is little data to support coronary artery intervention prior to transplantation in those with asymptomatic coronary artery disease.
Coronary artery disease is of crucial importance in patients with end-stage renal failure. Cardiovascular disease is recorded as the commonest cause of death in both dialysis patients and renal transplant recipients. While there is an increased risk of cardiovascular death in the dialysis population compared to the renal transplant population,1 even after renal transplantation, the risk of cardiac death remains significantly greater than that of the general population. Similarly, patients with chronic kidney disease (CKD) are at greater risk of cardiovascular death than those with normal renal function.2,3
There are a number of features of cardiac disease that are unique to patients with CKD and are likely associated with the uraemic milieu. These include accelerated cardiovascular disease which is likely due to both traditional risk factors such as hypertension, diabetes, smoking and dyslipidaemia, and factors associated with renal disease including hyperhomocystinaemia, hyperparathyroidism, an elevation of the calcium–phosphate product, fluid overload, uraemic toxins, inflammation and anaemia. Additionally, the risk of sudden cardiac death is markedly increased in patients with renal failure. This is likely to be due, at least in part, to uraemic cardiomyopathy and metabolic derangements resulting in cardiac arrhythmias.
There are well established guidelines in the general population for the management of coronary artery disease,4,5 however, similar guidelines have not been established in the renal population. This review examines the current published work on the detection of coronary artery stenoses (Table 1) in addition to summarizing the outcomes of revascularization in patients with kidney disease.
Table 1. Summary of revascularisation studies in CKD, dialysis and transplantation
|Manske et al.21||CKD and dialysis||Revascularization compared to medical treatment randomized controlled trial||26||Decreased events in revascularized group|
|Holzmann et al.22||CKD||CABG||6711||Mortality increased in CKD compared to general population|
|Gruberg et al.23||CKD||CABG||639||Mortality increased in CKD compared to general population|
|Lok et al.24||CKD||CABG||2077||Mortality increased in CKD compared to general population|
|van der Wal et al.25||CKD||CABG||358||Mortality increased in CKD compared to general population|
|Cooper et al.26||CKD||CABG||371 882||Mortality increased in CKD compared to general population|
|Akman et al.27||CKD and dialysis||CABG||CKD 55; dialysis 47||Mortality increased in CKD compared to general population|
|Chonchol et al.28||CKD||CABG||114||Mortality increased in CKD compared to general population|
|Naidu et al.31||CKD||Percutaneous angioplasty||192||Mortality and TVR increased in CKD|
|Best et al.32||CKD||Percutaneous angioplasty||2427||Mortality increased in CKD compared to general population|
|Sedighi et al.33||CKD||Percutaneous angioplasty||350||Mortality and TVR increased in CKD|
|Ting et al.34||CKD and dialysis||Percutaneous angioplasty||87 CKD; 24 dialysis||Mortality increased in CKD and dialysis compared to general population|
|Reinecke et al.35||CKD||Percutaneous angioplasty||573||Mortality increased in CKD compared to general population|
|Rubenstein et al.36||CKD||Percutaneous angioplasty||362||Mortality and cardiac events increased in CKD|
|Lemos et al.38||CKD||Coronary artery stenting||186||Mortality increased in CKD|
|Marzocchi et al.39||CKD||Coronary artery stenting||525||TVR and re-stenosis increased in CKD|
|Halkin et al.40||CKD||Coronary artery stenting||223||Reduced re-stenosis with drug-eluting stents|
|Szczech et al.41||CKD and dialysis||CABG compared to PCI||840 CKD; 407 dialysis||No survival difference in CKD; reduced mortality with CABG in dialysis|
|Hemmelgarn et al.42||CKD and dialysis||CABG compared to PCI||750 CKD; 662 dialysis||Improved survival with CABG and PCI compared to conservative treatment in dialysis patients|
|Stigant et al.43||CKD||Angioplasty compared to stenting||1622||Major cardiac events and TVR with stenting|
|Horst et al.44||Dialysis||CABG||65||Mortality increased in dialysis compared to general population|
|Krabatsch et al.45||Dialysis||CABG||71||Mortality increased in dialysis compared to general population|
|Wong et al.46||Dialysis||CABG||35||Increased blood transfusions dialysis population|
|Herzog et al.47||Dialysis||CABG||14 306||Increased mortality dialysis population; improved survival with CABG compared to angioplasty|
|Herzog et al.48||Dialysis||CABG compared to PCI compared to stenting||15 784||Increased mortality dialysis population; improved survival with CABG compared to angioplasty|
|Schoebel et al.49||Dialysis||Percutaneous angioplasty||20||Increased re-stenosis in dialysis population|
|Kahn et al.50||Dialysis||Percutaneous angioplasty||17||Increased re-stenosis in dialysis population|
|Agirbasli et al.51||Dialysis||CABG compared to PCI||252||Increased TVR in PCI|
|Rinehart et al.52||Dialysis||CABG compared to PCI||84||Increased TVR in PCI|
|Herzog et al.53||Transplant||CABG compared to PCI compared to stenting||2661||Reduced cardiac death and AMI in CABG compared to PCI|
ASSESSMENT OF CORONARY ARTERY DISEASE
Renal disease is an important risk factor for all-cause cardiovascular mortality, with annual mortality rates in US dialysis patients in excess of 200/1000 patient-years6 Despite this, cardiovascular assessment in asymptomatic patients is often only carried out on those who are being considered for kidney transplantation.7–9 Coronary artery screening for all patients listed for transplantation is expensive and time-consuming and screening practices are diverse. There are, however, some groups of patients who are clearly at higher risk of cardiovascular events. In particular, diabetics and patients with a history of cardiovascular events are at high risk of coronary artery disease.10,11 In addition, in those patients on dialysis, the duration of end-stage renal failure is strongly associated with the development of cardiovascular events12 while the degree of renal impairment correlates with cardiovascular system events in those with CKD2 and after transplantation.13
There are a number of investigations that can be used to screen for coronary artery disease. The most commonly used tests include myocardial stress tests and coronary angiography. Approximately 40% of end-stage renal failure patients will have angiographic evidence of significant coronary artery stenoses.14
Exercise electrocardiogram (ECG) testing is often used to identify patients at increased surgical risk of coronary artery disease in the non-renal population, however, there are few studies examining this screening modality in patients with renal failure. The predictive accuracy for the detection of coronary artery disease using exercise ECG is low in dialysis patients, with a sensitivity of only 35%.15 This is largely because of the inability of this patient group to exercise to a predictive capacity. Because of the historic poor performance of exercise stress testing, myocardial perfusion studies are commonly used. A recent meta-analysis16 showed that a positive myocardial perfusion study was significantly associated with a greater relative risk of myocardial infarction and cardiac death than a negative study. Myocardial perfusion studies can be performed using exercise or dobutamine stress echocardiography or thallium scintigraphy.
Coronary angiography remains the gold standard for the evaluation of coronary artery disease. Concerns, however, are often raised due to the invasive nature of the procedure and the risk of contrast nephropathy, in particular in patients who are not yet on dialysis. Coronary artery stenoses of more than 70% strongly predicted cardiac events at 4 years in comparison with a very low event rate in those without coronary artery disease.14
A recent study17 examined 300 consecutive patients with end-stage renal failure who were referred for transplant listing assessment. All patients underwent exercise stress testing and had an assessment of left ventricular function using cardiac MRI. Those with a high index of suspicion for coronary artery disease underwent coronary angiography and proceeded to percutaneous coronary intervention if indicated. The criteria for angiography and subsequent coronary revascularization were not fixed, but were dependant on clinical judgement. Only 68% of patients were able to attempt a standard exercise test. Thirty-nine percent of these were positive with ECG changes, chest pain or a blood pressure response suggesting underlying coronary artery disease. Ninety-nine patients underwent coronary angiography. Of these, over 60% had normal coronary arteries or mild coronary artery disease with stenoses less than 75%. Single- and double-vessel coronary artery disease accounted for 13.1% and 15.2% of subjects, respectively, while only 6.1% had triple-vessel or left main stem disease. Only 17 patients went on to have percutaneous coronary intervention or coronary artery bypass grafting (CABG).
In this study, the non-invasive and angiographic findings were examined in relationship to mortality. The ability to exercise was of prognostic importance with a significantly reduced survival in patients who were unable to exercise compared to those who were able to complete an exercise tolerance test. There was however no significant survival difference between those patients referred for angiography compared with those who were not, despite the higher perceived cardiovascular risk of patients referred for angiography. In addition, there was no apparent survival difference between those who underwent revascularization compared with those who underwent angiography without intervention. A multivariate analysis revealed older age, a history of diabetes, ischaemic heart disease and an inability to exercise more than 6 min as independent predictors of mortality. While a poor performance in an exercise tolerance test was predictive of mortality, invasive screening using angiography did not impact on survival.
Hence, while the detection of coronary artery disease can provide prognostic information and is often used to restrict listing for transplantation, there is currently no data proving that detection and treatment of coronary artery disease using revascularization, provides an actual benefit to the patient. Ongoing assessment of the utility of screening for renal transplantation needs to be undertaken.
REVASCULARIZATION: STABLE CORONARY ARTERY DISEASE
Chronic kidney disease
In comparison to the general population, in whom there are a number of trials comparing revascularization with medical therapy18–20 there is only one randomized controlled trial examining the efficacy of revascularization in patients with CKD.21 This paper examined patients with insulin-dependent diabetes (mainly type 1), who underwent coronary angiography as part of the assessment for transplantation listing. Twenty-six patients were randomized to either medical treatment or revascularization. This study demonstrated a significant increase in cardiac events and death in patients who were treated with medical therapy in comparison to the revascularization group. Unfortunately, this study was powered to enrol over 150 patients and recruitment was discontinued because of the excess events in the medically treated group after an interim analysis at 24 months, in addition to difficulties with patient recruitment. In addition, the group treated conservatively had a low rate of use of aspirin and beta-blockers; medications that in the general population, have been shown to prevent cardiac death in those with ischaemic heart disease.
There are a number of studies examining the outcomes of revascularization in patients with CKD. These have largely come from patient cohorts and registry data. In comparison to the general population, patients with CKD are at increased risk of both early and late mortality after CABG.22–28 Estimated GFR has been shown to be an independent predictor of mortality in patients undergoing CABG.29 In addition, the presence of CKD is associated with an increased incidence of postoperative complications30 compared to those with normal renal function.
Similarly, patients with CKD treated with percutaneous coronary interventions are at greater risk of mortality than the general population.31–36 In addition, there is an increased risk of both major cardiac events36 and re-stenosis with a requirement for target vessel revascularization.31,33,37
After coronary artery stenting, there is an increased incidence of mortality in patients with CKD as defined by creatinine clearance of less than 60 mL/min compared to those with normal renal function.38 CKD is an also an independent risk factor for re-stenosis and consequent target vessel revascularization.39 There does however appear to be a benefit from using drug-eluting stents in comparison with bare metal stents in patients with CKD. In particular, a subgroup analysis of a randomized control trial comparing slow-release paclitaxel-eluting stents compared with bare metal stents,40 showed a reduction in the requirement for further revascularization and a lower re-stenosis rate in patients with the drug-eluting stents.
There are few studies comparing CABG with percutaneous intervention in patients with CKD.41,42 No studies have demonstrated a survival benefit for coronary artery surgery compared to percutaneous intervention in those with CKD. There may, however, be a benefit of stenting compared to angioplasty without stenting in patients with CKD.43 In a study of 1616 patients with CKD (predominantly CKD grade II) which compared outcomes in eras of high (94%) compared to low (18%) stent use, coronary artery stenting was associated with fewer major adverse cardiac events, less repeat target vessel revascularization and fewer myocardial infarctions than percutaneous transluminal coronary angioplasty for all patients except those with a GFR of less than 29 mL/min.
There are no randomized controlled trials in this subgroup of patients. It is clear, however, that patients on dialysis have a greater perioperative mortality than those with normal renal function after CABG.44 In addition, long-term patient survival after coronary surgery is significantly worse than that of the general population.45 Dialysis patients are also more likely to require blood transfusions postoperatively than those with normal renal function.46 Two large registry studies have shown a 2 year survival of only 56% in dialysis patients after CABG.47,48
Similarly, dialysis patients are at greater risk than the general population of mortality after percutaneous coronary intervention34,37 and appear to have a higher risk of re-stenosis.49,50 There is little data on the use of stents in dialysis patients. It is unclear whether there is an increased incidence of re-stenosis in patients on dialysis with a disparity in the reports between trials.37,38
There are, however, a number of studies comparing the outcomes of percutaneous coronary intervention and coronary artery bypass surgery in dialysis patients with stable coronary artery disease. While small studies have shown no difference in mortality when comparing the outcomes after CABG and percutaneous coronary intervention (PCI),51,52 larger studies have demonstrated a reduced relative risk of all-cause and cardiac mortality in patients treated with CABG compared to angioplasty.41,47,48 This difference appears to occur in both diabetic and non-diabetic patients. Similarly, a significant reduction in the incidence of myocardial infarction has been observed in patients treated with coronary artery bypass surgery compared to angioplasty.47 Finally, due to the high risk of re-stenosis of coronary artery lesions in dialysis patients treated with percutaneous intervention, there is a markedly higher rate of target vessel revascularization after PCI compared to CABG.51,52
There are few studies examining the effects of coronary artery revascularization in the setting of kidney transplantation. The largest study examined outcomes in 2261 renal transplant patients53 who underwent coronary revascularization. This study demonstrated a 2 year patient survival of 82.7% after CABG with internal mammary artery grafting. Survival after coronary artery stenting and angioplasty in patients after kidney transplantation was also excellent. While there was no difference in the risk of all-cause and cardiac death between the three revascularization groups, there was a reduced risk of cardiac death and acute myocardial infarction in those treated with CABG using internal mammary grafts compared with percutaneous angioplasty suggesting that coronary artery surgery may be superior in this patient group. There is no data specifically examining the outcomes of coronary artery stenting in renal transplant recipients. In particular, there is no data examining the effects of re-stenosis and target vessel revascularization in this population.
Concern about the effect of revascularization on renal function after transplantation is often raised. Current data, however, suggests that there is a low risk of returning to dialysis after coronary artery revascularization.54
Revascularization prior to transplantation
The only trial specifically comparing medical treatment compared to revascularization in this setting has been described above.21 Unfortunately, there are no other randomized controlled studies examining revascularization compared to medical management prior to non-cardiac surgery in dialysis patients. There is, however, a recent study in patients with vascular disease who have a high risk of cardiac events associated with non-cardiac surgery.55 The Coronary Artery Revascularization Prophylaxis (CARP) trial examined the impact of prophylactic coronary revascularization in patients requiring major vascular surgery. In this study, patients were randomized to either revascularization using either CABG or angioplasty, or medical management. Revascularization was not associated with a benefit in patient survival with a 22% incidence of mortality in the revascularization group and 23% in the group who were medically managed. In addition, there was no difference in survival in any high-risk group examined. The results of this study concur with the guidelines from the American College of Physicians which do not recommend revascularization prophylactically in patients undergoing non-cardiac surgery, stating that there are clear potential risks and no evidence of either a short- or long-term benefit from revascularization.
REVASCULARIZATION: UNSTABLE CORONARY ARTERY DISEASE
In the general population with unstable coronary artery disease, urgent revascularization has been shown to be beneficial in terms of death and myocardial infarction.56 There have been no studies examining outcomes after revascularization of unstable coronary lesions in either dialysis or transplant patients. There have however, been post-hoc analyses of larger studies examining revascularization in the setting of unstable coronary artery disease in patients with CKD. In the post-hoc analyses of the Fast Revascularization in Instability in Coronary disease II trial (FRISC II),56,57 the incidence of death and/or myocardial infarction at 2 years in patients with a creatinine clearance of less than 69 mL/min was significantly reduced in those treated with early invasive intervention compared with those managed non-invasively (14.6% invasive group compared to 22.4% non-invasive group; P = 0.003). Indeed, the benefit of early invasive therapy was restricted to patients with a creatinine clearance of less than 90 mL/min. There were no patients in this study with CKD 5 and only six patients (0.2%) with CKD 4. A similar result has been shown in analyses of CKD patients after a non-ST elevation myocardial infarction.58
Coronary artery disease remains an important problem in patients with all degrees of renal impairment. The diagnosis of coronary artery disease can be effectively made using provocative stress testing and angiography, however, the optimal treatment of coronary lesions in patients with renal failure is not known.
There is currently no clear data to define which patients will benefit from revascularization. It is clear, however, that the risk of mortality is greater than that of the general population in patients with both CKD and end-stage renal failure treated with dialysis after coronary artery revascularization. In addition, there is no data to show a benefit in revascularizing patients with coronary disease in order for patients to be transplanted. Conversely, the outcomes of coronary revascularization after renal transplantation appear to be good with low mortality rates and a very low rate of significant decline in renal function. In both dialysis and transplant patients, there appears to be a benefit of CABG compared to angioplasty; however, this is based on observational data only.
It will be important to develop ongoing studies in this area to help define which patients will benefit from coronary revascularization and which mode of revascularization results in the best outcomes in patients with kidney disease.