Results

PATIENTS

The numbers of symptomatic patients were comparable in the two groups before the intervention. More patients in the control group than in the maintenance dialysis group had had a myocardial infarct before angioplasty (table 1). The cardiovascular risk profile in patients with end stage renal disease differed from controls, as there were significantly more risk factors per patient in the former, as well as a higher prevalence of diabetes mellitus and arterial hypertension. The underlying disease processes which led to end stage renal disease included diabetic nephropathy in seven patients, glomerulonephritis in eight, pyelonephritis in five, and polycystic disease in one.

LABORATORY VARIABLES

Quantitative assessment of cardiovascular risk factors reflected changes in the cardiovascular risk profile, as patients with renal disease showed increases in total cholesterol as well as reductions in HDL cholesterol (table 1). Increases in triglycerides and fibrinogen were highly significant in patients on maintenance dialysis compared with the controls.

QUANTITATIVE CORONARY ANGIOGRAPHY, ANGIOPLASTY, AND RESTENOSIS

The predominant target vessel for intervention was the left anterior descending coronary artery, and there were no significant differences between the two groups in the complexity and angulation of the stenoses that were dilated (table 2). Target vessels in patients with end stage renal disease were smaller, as indicated by the differences in reference diameter and minimum luminal diameter, but stenoses were comparable in their severity (per cent diameter stenosis) and location (proximal, middle, or distal part of a major vessel).

Angiographic restenosis, defined by the presence of a haemodynamically relevant stenosis (> 50% luminal diameter) was present in 60% of patients with renal disease and in 35% of controls on angiographic follow up but did not differ between groups, probably because of the small sample size (table 2) Per cent diameter stenosis showed a statistical trend towards a higher average degree of stenosis in the group with renal disease at the time of follow up.

Clinical restenosis, as defined by recurrence or aggravation of angina, occurred in 65% of patients with renal disease and in 35% of the controls. While the diagnostic sensitivity of clinical symptoms for the occurrence of angiographic restenosis was comparable in the two groups (75% in patients with renal disease and 71% in controls), diagnostic specificity was higher in patients on maintenance dialysis (85% versus 63%; table 2).

Analysis of quantitative angiographic variables for both groups combined showed that the severity of the coronary stenosis (per cent diameter stenosis) before the intervention was positively correlated with acute luminal gain (r = 0.57, p < 0.001) and acute luminal gain was positively correlated with late luminal loss (r = 0.39, p = 0.05) indicating that the severity of vessel injury is a promoter of restenosis. Procedural variables such as the size of the balloon, maximum inflation pressure, and total time of inflation were not related to restenosis.

There were no significant correlations between late luminal loss and fibrinogen or lipid values. Discriminant analysis showed that minimum luminal diameter before angioplasty (r = −0.79) had the highest influence on the occurrence of angiographic restenosis when analysed for both groups combined, followed by fibrinogen (r= +0.34), luminal vessel size as defined by the diameter of the reference segment before angioplasty (r = +0.32), and total cholesterol (r = +0.20).

Discussion

In this first controlled study which included age and sex matched patients without renal disease, the rate of angiographic restenosis in patients with renal disease was 60%, compared with 35% in controls. Results from this study indicate that prothrombotic factors and procedural variables—vessel size in particular—may be of relevance for angiographic restenosis in patients with end stage renal disease.

LABORATORY VARIABLES

Fibrinogen concentrations were significantly raised in patients with end stage renal disease compared with the controls, and statistical analysis showed that this haemostatic factor affected the rate of angiographic restenosis. Fibrinogen is the substrate of thrombin and is a major determinant of platelet aggregation and rheological blood properties.14 15 Linear interrelations between fibrinogen, thrombin generation, and enhanced endogenous fibrinolytic activity have also been demonstrated.16 17Patients on maintenance dialysis have been found to have a higher plasma fibrinogen than patients without renal disease,18which suggests a marked procoagulant disease state in the former.19 Therefore patients with end stage renal disease share some of the haemostatic features of patients with acute coronary syndromes,20 in whom there is also an increased risk of restenosis following coronary angioplasty.21 22 As secondary thrombosis following mechanical injury plays a major role in the pathogenesis of restenosis,23-25 it is conceivable that a systemic hypercoagulable disease state contributes to this process in patients with end stage renal disease.

Indices of lipid metabolism were pathologically altered in patients with end stage renal disease in comparison with the controls. It has been shown previously that HDL cholesterol is reduced in the general population of patients with restenosis,25 while there is no convincing evidence that increases in LDL cholesterol or triglycerides are of particular relevance.

PROCEDURAL VARIABLES IN CORONARY ANGIOGRAPHY AND ANGIOPLASTY

Previous studies which evaluated the follow up of patients with renal disease who underwent PTCA are not comparable with ours because of the heterogeneity of the cohorts chosen and because of different clinical and angiographic end points8-10 (table 3). In these studies clinical restenosis, presumably defined by recurrence or aggravation of angina pectoris, occurred in 60% to 82% of the cases. While data presented by Kahn et al 9 and by Ahmed et al 8 imply that angina is a very good indicator of angiographic restenosis (all symptomatic patients investigated angiographically showed significant renarrowing), the data of Rinehart et al 10 suggested that angina predicted restenosis in 69% of cases. The latter results are more comparable with our current findings, where angina had a sensitivity of 75% in detecting angiographic restenosis. It should be borne in mind, though, that angina was present in 85% of patients with end stage renal disease before the intervention. Therefore these results only reflect the potential for clinical symptoms to detect restenosis in symptomatic patients; they are not relevant to the primary detection of coronary artery disease where increased numbers of asymptomatic patients are to be expected because of the high prevalence of neuropathy.26

The rate of angiographic restenosis is lower than that reported in previous studies (69% to 100%).8-10 This is probably a result of selection bias, as in these studies only patients with clinical symptoms were re-evaluated angiographically. Given the high specificity of clinical symptoms for the occurrence of angiographic restenosis in patients with end stage renal disease, as documented by our study, the restenosis rate would have been lower in the other studies if all the patients had been followed up angiographically. Furthermore in earlier investigations restenosis was assessed visually while this is the first study employing computer assisted quantitative coronary angiography at baseline and on follow up. It is known that visual evaluation of coronary stenoses is particularly unreliable in the medium range (between 50% and 90% diameter stenosis),27 which is also the predominant range in which restenoses occur. It is therefore quite likely that the restenosis rate was overestimated in previous investigations.

In the patients with end stage renal disease in our study the changes in quantitative angiographic variables reflected the smaller luminal vessel size and the smaller minimum luminal diameter before angioplasty compared with the controls, which have both been described as predictors of restenosis.28 29 Diffuse thickening of the coronary intima and media has been shown to be a dominant feature in experimental models of uraemia.30 This has recently been confirmed in human coronary arteries and in internal mammary arteries from patients with end stage renal disease, harvested either postmortem or intraoperatively (K Amann, personal communications). This may account for smaller luminal diameters despite comparable locations of the stenosis in the coronary arterial system in patients with end stage renal disease, as the luminal view on coronary angiography gives an incomplete reflection of coronary atherosclerosis.31

The acute gain in lumen size did not differ between the two groups. This suggests a more severe degree of vessel injury in relation to vessel size in the patients with end stage renal disease. This is supported by the finding of a greater degree of late luminal loss in patients with renal disease, though that did not reach statistical significance. In conjunction with increased wall stiffness from diffuse narrowing of the vascular wall, this may have led to an increased amount of secondary thrombosis and to the induction of more pronounced proliferative processes.32-34

LIMITATIONS OF THE STUDY

The number of patients included in this retrospective study was small and the quality of the data therefore does not allow us to draw the conclusions that might be derived from a large scale prospective trial. As PTCA is not often performed in patients with end stage renal disease, as indicated by the small case numbers reported from other large centres, the number of patients in this investigation probably reflects the best that can be achieved by a single centre. Therefore prospective trials with a multicentre design are warranted to draw more valid conclusions.

In this study, results based on angiographic vascular morphology have to be viewed with particular care. The size of the target vessel and the minimum luminal diameter were smaller in patients with end stage renal disease than in the controls. Since these two features are well accepted predictors of restenosis in the general population, this could represent an error in the selection of the control group. On the other hand a more pronounced narrowing of the vascular lumen may suggest specific features in the pathology of atherosclerosis in patients with end stage renal disease. Given that the control group was also representative in terms of cardiovascular risk profile, our results probably reflect the true situation presenting to the clinician. Definitive answers will only be provided by future investigations with more specific imaging techniques like coronary intravascular ultrasound or angioscopy. Such techniques may clarify the role of vascular calcium content, the lumen to wall ratio, and primary thrombosis at the site of intervention as potential vascular risk factors for coronary restenosis in patients with end stage renal disease.

CLINICAL IMPLICATIONS

Results from this study imply that procedural and prothrombogenic factors, which are regarded as having an impact on restenosis in the general population, may also contribute to the pathogenesis of restenosis following PTCA in patients with end stage renal disease. Revasularisation procedures which enlarge the vascular lumen more completely, for example stent implantation,35 36 may therefore be of particular therapeutic benefit. Although the prolonged administration of antithrombotic treatment such as aspirin, coumarins, and heparin has not proved to be successful in preventing restenosis in the general population, patients with end stage renal disease are a promising target group for novel antithrombotic interventions because of their high prothrombotic risk. It is therefore premature to rule out PTCA as a revascularisation procedure in patients with end stage renal disease, and prospective interventional trials are warranted which address the specific risk factors in this cardiovascular high risk group.