15th December 2017, Volume 130 Number 1467

Helen Pilmore, Mark Webster, Karishma Sidhu, Gajan Srikumar

The incidence of end-stage renal failure (ESRF) is increasing worldwide. Although renal transplantation improves survival compared with dialysis, cardiac disease remains a leading cause of death in patients after a kidney transplant.1 Patients who are assessed for renal transplantation often undergo non-invasive cardiac testing to determine their suitability both for the transplant procedure and to determine their risk of cardiac events in the post-transplantation period. If provocative cardiac stress tests are positive, patients generally undergo diagnostic coronary angiography. Some patients with disease in major coronary vessels will undergo revascularisation by percutaneous intervention (PCI) with stenting or coronary artery bypass grafts (CABG). These patients may then be considered for a possible renal transplant.

Coronary angiography is also undertaken in patients with chest pain and in those presenting with an acute coronary syndrome. Although there is little data specifically in patients with ESRF, in the wider population with coronary disease an early invasive strategy with revascularisation as appropriate is better than an initial conservative approach in patients with non-ST elevation myocardial infarction,2 and primary PCI is better than thrombolysis in those presenting with ST elevation myocardial infarction.3

In patients on dialysis, mortality after coronary revascularisation is significantly higher than that of the general population. In an analysis of a large cohort of dialysis patients using USRDS data, two-year survival following CABG and PCI was much lower in dialysis patients compared to that reported in the general population, with a two-year survival after CABG of only 55%.4

Overall, the benefits of coronary artery revascularisation are unclear in patients with ESRF, and there is little data comparing revascularisation with medical management. We examined the outcomes of dialysis patients undergoing angiography, comparing survival of those managed medically with those undergoing revascularisation. We assessed both current mortality and major adverse event rates to better understand outcomes in this high-risk population.

Methods

A retrospective analysis was conducted on patients with ESRF on dialysis undergoing coronary angiography at Auckland City Hospital between 2003 and 2012. All patients undergoing angiography during this period were identified. Those on dialysis were identified from the ANZDATA registry, and cross checked with patients in the cardiac catheterisation laboratory database. Only patients with angiograms undertaken after commencement of dialysis were included. Patients were excluded if they commenced dialysis during the same admission or after the last angiogram, or if a diagnostic coronary study was not performed, eg, those having only a right heart study.

Demographic data including age, gender, ethnicity and angiogram dates were obtained from the cardiology database. Data for mortality, cause of renal failure and date of dialysis were provided by the ANZDATA registry. A manual review of hospital records was undertaken to collect data on the presence of diabetes, angiogram results, left ventricular ejection fraction, intervention, listing for transplant, previous transplant and cardiovascular outcomes. Angiography data included indication, number and identification of major vessels diseased (left main, left anterior descending, circumflex/major obtuse marginal and right coronary) and the left ventriculogram ejection fraction (if undertaken). The number of vessels diseased was assessed as the number of major coronary arteries with a greater than 50% diameter stenosis. Indications for angiography were divided into myocardial infarction (ST elevation or non-ST elevation), chest pain (including angina), transplant assessment and other indications (arrhythmia, valvular heart disease, syncope and unknown indications). Intervention data included categorising the management occurring as a result of the initial coronary angiogram as either medical management, PCI or CABG. All decisions regarding proceeding with medical therapy or CABG in patients with triple vessel disease were made by the cardiology service in association with cardiac surgical services and were assessed on an individual basis. Medication use was assessed using the discharge summary at the time of coronary angiography. Patients were assessed for use of aspirin, beta blockers, statins, angiotensin converting enzyme (ACE) inhibitors/angiotensin receptor blockers (ARBs) and additional antiplatelet agents. Patients were assessed as to whether they were listed for transplantation after angiography, and whether they underwent kidney transplantation. Major adverse cardiovascular events (MACE) were defined as myocardial infarction, stroke, amputation or peripheral revascularisation occurring any time after the coronary angiogram.

For patients with multiple angiograms, to avoid double counting outcomes and interventions, the first angiogram following commencement of dialysis was used for all subsequent outcome measures and intervention data.

Statistical analysis

Baseline data are reported as mean and one standard deviation (SD), or frequencies with percentages (%). Survival duration is reported as median with interquartile range (IQR). Kaplan-Meier curves were generated to depict the distributions of survival and freedom from MACE, by intervention. The survival curves were compared using the log-rank test. Survival rates at two years and five years after the first angiogram were compared between interventions using the two-sample Z test. Univariable and multivariable Cox proportional hazards regression were conducted to determine the risk factors for death and MACE. The Chi-squared test was used to assess the relationship between intervention and medication use. Statistical analyses were performed using the statistical package SAS version 9.3 (SAS Institute, Cary, NC). All p-values resulted from two-sided tests and a p-value of <0.05 was considered significant.

Results

Patient characteristics and angiogram results

One thousand seven hundred and fifty-six angiograms were undertaken on 1,381 patients with chronic kidney disease (CKD) Stages 3–5 identified in the cardiac catheterisation laboratory database (Figure 1). Three hundred and fifty-four patients were on dialysis. Sixty-five patients were excluded from the analysis, most because they commenced dialysis during the same admission or after their last angiogram.

Figure 1: Recruitment of the study population.

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Two hundred and eighty-eight patients, having 382 angiograms, were included in the study (Table 1). The mean number of angiograms per person was 1.3. The mean age at the time of the first angiogram following dialysis was 59+/-11 years. More than half (59%) of the patients had diabetes mellitus. Most coronary angiograms were undertaken after a diagnosis of myocardial infarction. However, 21% of patients underwent diagnostic angiography as part of assessment for kidney transplantation. The median follow-up was 3.1 years (range 2.0–10.7 years). Less than 30% of patients had no significant coronary artery stenoses while 37% had greater than 50% stenosis in all three coronary arteries.

Table 1: Baseline characteristics of participants (participants with no intervention are not included in baseline comparison).

Intervention

CABG

Stent

Medical management

Total

Chi Squared P

Age [years], mean ± SD

58.4±8.4

61.2±12.2

60.6±10.2

59.3±11.3

 

Gender

Male, n (%)

22 (73)

41 (67)

105 (70)

193 (67)

0.8364

Ethnicity

European, n (%)

8 (27)

24 (39)

48 (32)

100 (35)

0.6831

Māori, n (%)

8 (27)

18 (30)

49 (32)

92 (32)

 

Pacific, n (%)

12 (40)

14 (23)

40 (26)

71 (25)

 

Other, n (%)

2 (7)

5 (8)

14 (9)

25 (9)

 

Diabetes, n (%)

19 (63)

34 (56)

100 (66)

169 (59)

0.3578

Cause of renal failure

DM, n (%)

14 (47)

30 (49)

87 (58)

143 (50)

0.2495

GN, n (%)

9 (30)

12 (20)

37 (25)

78 (27)

 

Other, n (%)

7 (23)

19 (31)

27 (18)

67 (23)

 

Duration of dialysis [days], median

760

926

983

912

 

Smoking status 

Never, n (%)

5 (17)

5 (8)

23 (15)

39 (13)

0.3401

Previous, n (%)

11 (37)

15 (25)

52 (34)

96 (33)

 

Current, n (%)

8 (27)

26 (43)

42 (28)

89 (31)

 

Unknown, n (%)

6 (20)

15 (25)

34 (23)

64 (22)

 

Indication

Transplant, n (%)

5 (17)

9 (15)

18 (12)

60 (21)

0.5827

MI, n (%)

13 (43)

28 (46)

64 (43)

106 (37)

 

Chest pain, n (%)

5 (17)

18 (30)

43 (28)

74 (26)

 

Other, n (%)

7 (23)

6 (10)

26 (17)

48 (17)

 

Number of vessels with >50% stenosis

 0, n (%)

0

0

41 (27)

86 (30)

<0.0001

 1, n (%)

1 (3)

17 (28)

22 (15)

41 (14)

 

 2, n (%)

7 (23)

21 (34)

25 (17)

53 (18)

 

 3, n (%)

22 (73)

23 (38)

63 (42)

108 (37)

  

Intervention

Ninety-one (32%) patients underwent revascularisation as their primary intervention following the initial angiogram (61 PCI and 30 CABG), 151 (52%) patients were treated medically and 46 (16%) patients required no specific coronary disease management.

Of the 60 (21%) patients who underwent diagnostic angiography as part of transplant assessment, 29 (48%) had evidence of coronary artery disease. Of these patients, eight (28%) underwent CABG, seven (24%) underwent PCI and 14 (48%) had medical management.

Mortality

One hundred and seventy (59%) patients died during the follow-up period. Eighty-two (48%) patients had a cardiovascular cause of death, 31 (18%) patients died due to infection, 22 (13%) patients due to withdrawal of dialysis, four (2%) patients due to malignancy, 11 (6%) patients due to other causes and 20 (12%) patients with an unknown cause of death.

The median survival was 3.3 (IQR 2.1–5.3) years after the initial angiogram in patients undergoing CABG, 2.9 (IQR 1.5–5.4) years in patients who were treated with PCI and 2.9 (IQR 1.3–5.5) years in patients managed medically. There was no difference in survival between the treatment modalities for the entire cohort (Figure 2A), nor in those patients with triple vessel disease (Figure 2B).

Figure 2: Kaplan-Meier (KM) curves for overall survival for all vessels by intervention (A). KM curves for overall survival in triple vessel disease by intervention (B).

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When comparing survival according to the number of coronary vessels with a greater than 50% stenosis, there was a lower survival rate for patients with three vessel disease, compared with those having no significant coronary artery disease. Survival was not reduced in those with one or two diseased vessels (Figure 3).

Figure 3: Kaplan-Meier (KM) curves for overall survival in all patients by number of vessels.

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Predictors of all-cause mortality

All-cause mortality was higher with increasing age, the presence of diabetes mellitus and the presence of triple vessel disease (Table 2). Those listed for transplantation after angiography and undergoing kidney transplantation had a lower subsequent risk of death.

Table 2:Independent factors associated with all-cause mortality (grey) and major adverse cardiac events (white).

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*Other indications for angiography include arrhythmia, valvular heart disease, syncope and unknown indications. 

On a multivariable analysis the only factor associated with survival was transplantation status (Table 3).

Table 3: Multivariable analysis of factors associated with mortality (grey) and major adverse cardiac events (white). 

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Major adverse cardiac events

Factors predicting MACE were increasing age, diabetes and triple vessel disease, while undergoing angiography as a part of transplantation assessment and being transplanted or listed for transplantation were associated with improved survival (Table 2). There was no difference in the rate of MACE between patients who underwent a revascularisation procedure and those who were medically managed (HR 0.928; 95% CI 0.694–1.242; p=0.6163). There was also no difference in the rate of MACE comparing patients treated with medical management and PCI (HR 0.971; 95% CI 0.687–1.373; p=0.869), or medical management and CABG (HR 0.677; 95% CI 0.395–1.163; p=0.159) (Figure 4).

Figure 4: Kaplan-Meier (KM) curves for MACE in all vessels by intervention (A). KM curves for MACE in triple vessel disease by intervention (B). 

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Medication

Medications were recorded in 286 (99%) patients at discharge after their first angiogram. Seventy-three percent of patients were prescribed beta blockers, while 88% were given aspirin and 82% prescribed a statin (Table 4). There was no significant difference in the use of medications in patients treated medically compared to those treated with PCI or CABG, except for an increased use of dual antiplatelet therapy in patients undergoing PCI.

Table 4: Use of medications at discharge following first angiogram, %.

 

Overall

Medical management

PCI

CABG

p-value

Beta blockers

73

71

80

70

0.4319

Aspirin

88

84

97

90

0.0395

Statin

82

82

80

83

0.8942

ACE inhibitor

53

57

54

33

0.0549

Other antiplatelet

39

21

95

17

<0.0001 

Repeat angiography

Sixty patients underwent more than one coronary angiogram (mean 2.5 procedures). In those patients who had a normal coronary angiography, 9% required a second angiogram. In comparison, 34% of those undergoing PCI as primary treatment after the first angiogram required subsequent coronary angiography, compared with 17% and 23%, respectively, of those treated initially with medical management or with CABG.

Discussion

This study, evaluating an all-comers population of patients with ESRF undergoing coronary angiography, found no significant difference in outcomes between the one-third of patients revascularised by either PCI or CABG, and the two-thirds who were managed medically. A full spectrum of patients were enrolled, including those with chest pain, those presenting with an acute coronary syndrome and those being evaluated for possible renal transplantation.

The results contrast with findings suggesting improved survival with revascularisation. The only randomised, controlled trial comparing revascularisation and medical management in patients with renal failure and coronary artery disease was undertaken over two decades ago. Only 26 patients with asymptomatic coronary disease and diabetes being assessed for renal transplant were enrolled; 10 of 13 patients treated medically reached a cardiovascular endpoint after 8.4 months of follow-up, compared with just two of 13 revascularised patients. The trial was limited by the use of short-acting calcium channel blockers, sub-optimal aspirin use, the very small study population and short follow-up.5 An analysis from the APPROACH study6 evaluated 662 dialysis patients undergoing cardiac catheterisation, comparing survival in patients having CABG, PCI and no revascularisation. Adjusted eight-year survival rates in those having CABG (45%) or PCI (41%) were better than in those not revascularised (30%). Reddan et al found that, in a small cohort of 69 dialysis patients, CABG but not PCI was associated with a survival benefit, compared with medical management.7

In contrast, other authors have reported similar findings to our study. A single-centre, prospective observational study found no difference between patients with ESRF being assessed for kidney transplant who underwent PCI or CABG, versus those who were medically managed.8 Another study by De Lima et al9 showed that, in patients with chronic kidney disease and significant coronary artery disease, survival for patients on medical treatment at one, three and four years was 91%, 71% and 59%, which was similar to survival in those who underwent revascularisation (PCI or CABG) at 93%, 67% and 57%, respectively.

In the general population of patients with stable coronary disease, CABG has been shown to have a survival benefit over medical treatment in those with left main stenosis and those with three vessel disease and left ventricular dysfunction. Outcomes following CABG and PCI are similar, except in patients with extensive coronary disease and diabetes, in whom CABG is associated with better longer-term outcomes.10 It is difficult extrapolating the results to patients with ESRF because they were almost invariably excluded from these trials. In addition, there are specific challenges to both CABG and PCI in ESRF. Heavy and extensive coronary artery calcification is common in ESRF, and may make surgical graft anastomosis technically difficult, and may cause difficulties with stent delivery and achieving full stent expansion.

In patients presenting with a non-ST elevation acute coronary syndrome, a strategy of early angiography and revascularisation is associated with better clinical outcomes than a conservative approach reserving angiography to those with ongoing symptoms. Further, the absolute gain with early angiography is greater in higher-risk than lower-risk patients. In those with ST elevation myocardial infarction, revascularistion by primary percutaneous coronary intervention improves survival, compared with thrombolysis. It remains uncertain whether these findings are applicable to those with ESRF, because they were excluded from most of the trials.11

The guidelines for coronary revascularisation in dialysis patients recommend adherence to the guidelines for the general population, although decisions made regarding revascularisation should take into account the perioperative mortality risk, which is higher than the general population.12

Our study confirms that there is a poor survival in all dialysis patients compared to the general population. The two-year survival for all patients following initial angiography was 69%, and five-year survival was 29%. Data from the ERA-EDTA registry13 shows that overall survival in dialysis patients following initiation of dialysis is poor with a two-year survival of 68% and five-year survival of 40%. For patients in the general population with triple vessel disease, the five-year survival is 89% following CABG and 85% following PCI.14 This is much higher than survival in dialysis patients undergoing revascularisation with a five-year survival after CABG of 28% and after PCI of 24%.15

Compared to those with no coronary disease, there was significantly worse survival for patients with three vessel disease. In the general population of patients with coronary artery disease, survival is much lower in those with triple vessel disease. The four-year survival for medically treated patients with no disease is around 97%, whereas survival in those with one and two vessel disease is 92% and 84%, respectively, and only 68% in those with three vessel disease.16

We found that the use of cardioprotective medications was high with over 80% of patients treated with medical management or revascularisation receiving aspirin and statins, in addition to a high use of beta blockers. There was no difference between groups, except for dual antiplatelet therapy being higher in the PCI group, as expected. Over a third of patients treated initially with PCI required repeat angiography with fewer in both the CABG and medically managed groups. This is consistent with previous reports demonstrating a high requirement for repeat target vessel revascularisation in patients with ESRF treated.17

Kidney transplantation was associated with improved survival and reduced MACE. This has previously been demonstrated in multiple studies, highlighting the benefits of transplantation even in those with coronary artery disease.18 Others have demonstrated that kidney transplantation confers a survival benefit in patients with significant CAD.19 Despite the improved survival with transplantation, it remains unclear whether revascularisation prior to kidney transplantation provides an additional benefit. Additionally, it must be noted that in general the superior survival in transplant recipients is, at least in part, due to patient selection.

A strength of our study is the inclusion of all patients undergoing angiography, reflecting the real-world patient population. The study included not only patients with ESRF without evidence of CAD evaluated for transplant but also patients requiring clinical management for myocardial infarction, angina or other indications. There was a long period of follow-up, which was complete, with medication data available in over 99% of patients. All patients were from a single centre.

The major study limitation is that the treatment groups were not randomly allocated, and it is not possible to adjust for all potential confounders. The small size of subgroups limits the ability to draw conclusions from these patient cohorts. Some patients had multiple angiograms and further revascularisation procedures, including cross-over from PCI to CABG and vice versa, which may cause confounding.

Conclusion

Our study found no difference in survival between patients with ESRF undergoing revascularisation and those managed medically in a group where the use of cardioprotective medication was high. Only kidney transplantation was associated with a reduction in death and cardiac events.

The high mortality rate in patients with ESRF and coronary disease and the modest evidence base for the optimal treatment of coronary disease lead to clear equipoise for a randomised trial randomly comparing different treatment strategies.

Summary

Coronary artery disease is common in patients with end-stage renal failure (ESRF). We assessed survival and cardiovascular outcomes in patients with ESRF undergoing coronary angiography and then having coronary artery bypass graft (CABG) surgery, percutaneous coronary intervention (PCI) or medical management. Two hundred and eighty-eight patients had a total of 382 diagnostic coronary angiograms. There was no significant difference in survival between treatment modalities in the entire cohort, nor in the 108 patients with severe coronary artery disease. Similarly, there was no difference in the incidence of major adverse cardiac events, comparing medical management with revascularisation.

Abstract

Aim

Coronary artery disease is common in patients with end-stage renal failure (ESRF). However, there is little evidence that revascularisation improves outcomes, compared with medical management. This study assessed survival and cardiovascular outcomes in patients with ESRF undergoing coronary angiography and then having coronary artery bypass graft (CABG) surgery, percutaneous coronary intervention (PCI) or medical management.

Method

Survival and major adverse cardiac events (MACE) were examined in all patients with ESRF who underwent coronary angiography at Auckland City Hospital between 2003 and 2012. Outcomes of patients who underwent revascularisation (CABG or PCI) were compared with those managed medically.

Results

Two hundred and eighty-eight patients with ESRF had a total of 382 diagnostic coronary angiograms. Ninety-one (32%) patients underwent revascularisation (61 PCI, 30 CABG), with the other 197 (68%) treated medically or requiring no specific cardiac treatment. The median survival was 3.3 (IQR 2.1–5.3) years in patients undergoing CABG, 2.9 (IQR 1.5–5.4) years in patients treated with PCI and 2.9 (IQR 1.3–5.5) years in patients managed medically. There was no significant difference in survival between treatment modalities in the entire cohort, nor in the 108 patients with triple vessel disease. Similarly, there was no difference in the incidence of major adverse cardiac events, comparing medical management with revascularisation.

Conclusion

There was no apparent survival advantage with revascularisation by either CABG or PCI, compared with medical management, in patients with ESRF undergoing coronary angiography. This study confirms the poor prognosis of patients with ESRF and coronary disease. Observational studies cannot control for all potential confounders; randomised trial data are needed to guide optimal management of this high-risk patient cohort.

Author Information

Helen Pilmore, Department of Renal Medicine, University of Auckland, Auckland;
Mark Webster, Cardiology, Auckland; Karishma Sidhu, Biostatistics, Auckland City Hospital, Auckland; Gajan Srikumar, University of Auckland, Auckland.

Acknowledgements

This study was supported partly by a research grant from ADHB and A+ Trust awarded to Gajan Srikumar. 

Correspondence

Dr Helen Pilmore, Department of Renal Medicine, Auckland City Hospital, 2 Park Road, Grafton, Auckland 1023.

Correspondence Email

hpilmore@adhb.govt.nz

Competing Interests

Dr Srikumar reports grants from ADHB & A+ Trust during the conduct of the study.

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