Stage of chronic kidney disease and severity of coronary heart disease manifestation

Abstract

A recent study suggested that patients with chronic kidney disease (CKD) with a glomerular filtration rate (GFR) < 45 ml/min/1.73 m² are more likely to present with acute myocardial infarction (AMI) than with stable exertion angina. Thus, the degree of renal impairment seems to be related to the presentation of coronary heart disease (CHD). In this context, there is evidence indicating that statins decrease the excess risk for AMI and other CHD-related events in patients with CKD (although the benefit may depend on the stage of CKD). This effect might be attributed to stabilization of atherosclerotic plaques, which seem to be more vulnerable if CKD is present. Thus, statin treatment in early CKD, a condition considered to be a CHD equivalent by several guidelines, is likely to minimize the risk for CHD events.

Keywords::

• chronic kidney disease
• coronary heart disease
• dyslipidaemia
• myocardial infarction
• statins

Chronic kidney disease (CKD) affects > 20 million people in the USA (∼ 13% of the population); 8 million have stage 3 CKD (estimated glomerular filtration rate, eGFR, 30 – 59 ml/min/1.73 m²) and 500 000 have end-stage renal disease (ESRD) requiring renal replacement therapy [1]. There is an even higher prevalence of CKD in Japan [2].

Data from epidemiological and cohort studies in the USA, Europe and Japan, as well as interventional studies, have shown that CKD is an independent risk factor for cardiovascular disease (CVD) [3-8]. In those with ESRD, the risk of CVD death is 30 times greater than that of the general population [9] (the stages of CKD are listed in Table 1).

Table 1. Stages of chronic kidney disease.

	Description	GFR (ml/min/1.73 m^2)
Stage 1	Kidney damage with normal or increased GFR	≥ 90
Stage 2	Kidney damage with mildly decreased GFR	60 – 89
Stage 3	Moderately decreased GFR	30 – 59
Stage 4	Severely decreased GFR	15 – 29
Stage 5	Kidney failure	< 15 or dialysis

GFR: Glomerular filtration rate.

This evidence led guidelines from Canada [10] and Europe [11] to include CKD among coronary heart disease (CHD) equivalents [12]. The eGFR threshold that defines increased CVD risk has been identified as < 60 ml/min/1.73 m², while at < 30 ml/min/1.73 m² there is a doubling of CVD risk [13].

Despite the recognition of CKD as a CVD risk factor, data on the relationship between CKD stage and severity of CHD are scarce. In this context, a recently published post hoc analysis of the ADVANCE (atherosclerotic disease, vascular function and genetic epidemiology) study [14] provides some insight. From the 11 140 patients, 803 participants had an acute myocardial infarction (AMI), and 419 developed stable exertion angina and had baseline eGFRs < 130 ml/min/1.73 m² [14]. A strong, graded, independent association was found between reduced eGFR and presenting with AMI (p < 0.001 for trend). In patients who had an eGFR < 45 ml/min/1.73 m² there was a hazard ratio (HR) of 3.82 (95% confidence interval (CI) 1.55 – 9.46) for AMI compared with those with an eGFR > 90 ml/min/1.73 m². These data indicate that eGFR is a predictor of the severity of initial CVD manifestation with a threshold of 45 ml/min/1.73 m² [14], which is lower than the threshold for any manifestation of CVD (60 ml/min/1.73 m²). Thus, more advanced stages of CKD may be related to mechanisms that promote atherosclerotic plaque rupture, thrombosis and subsequent AMI [14].

We carried out a post hoc analysis of the GREACE (Greek atorvastatin and CHD evaluation) study [15], an open-label, prospective, randomized, controlled, secondary prevention and target-driven study (n = 1600 CHD patients). Statin-untreated patients with an eGFR < 45 ml/min/1.73 m² (n = 109) compared with those with an eGFR of 90 – 120 ml/min/1.73 m² (n = 196, reference group) had a risk ratio for subsequent CHD presentation as AMI of 2.99 (95% CI 1.31 – 6.66; p = 0.022). For unstable angina the risk ratio was 4.12 (CI 0.89 – 7.86; p = 0.083), and for revascularization the risk ratio was 3.64 (95% CI 1.02 – 6.92; p = 0.041). This excess CVD risk was ameliorated by statin treatment (a total of 869 participants were on statins). Patients with an eGFR < 45 ml/min/1.73 m² (n = 97) compared with those with an eGFR of 90 – 120 ml/min/1.73 m² (n = 208, reference group) had a risk ratio for AMI of 1.32 (95% CI 0.38 – 4.63; p = 0.29), for unstable angina a risk ratio of 1.24 (95% CI 0.25 – 3.2; p = 0.43) and for revascularization a risk ratio of 1.45 (95% CI 0.44 – 3.9; p = 0.35). These findings indicate that patients with CKD benefited more from statin (mainly atorvastatin) treatment in terms of subsequent major CHD events than those with normal renal function [16]. This finding was confirmed by the TNT (treating to new targets) trial (n = 10 001 CHD patients) [7]. Patients with stage 3 CKD (n = 3107) had a relative risk reduction in the composite primary end point (CVD death and major events) of 32% (p = 0.0003), while patients with normal renal function (n = 6549) had a marginally significant relative risk reduction of 15% (p = 0.049) [7]. TNT compared two atorvastatin doses (80 vs 10 mg/day).

The primary prevention ATTEMPT (assessing the treatment effect in metabolic syndrome without perceptible diabetes) study included 1123 patients with metabolic syndrome, free of diabetes or CVD at baseline [17,18]. ATTEMPT involved a multifactorial treatment built around target-based treatment with atorvastatin. Half of the patients (group A) had a low-density lipoprotein cholesterol (LDL-C) target of < 100 mg/dl (mean atorvastatin dose 32 mg/day) and the other half (group B) < 130 mg/dl (mean atorvastatin dose 27 mg/day) [17]. In group A there was only one non-fatal myocardial infarction after a 40-month follow-up. By contrast, in group B there was one CVD death and 12 nonfatal CVD events, instead of the 35 – 50 expected by calculating CVD risk [17]. In this group, the all major CVD events end point had a marginal inverse graded association with GFR as this was reduced from 120 to 30 ml/min/1.73 m² (p = 0.062 for trend). No single association was significant, probably because of the small number of CVD events.

Therefore, aggressive treatment with a statin might ameliorate the presentation of initial or subsequent CHD manifestation. These findings are in agreement with those from the entire ADVANCE population (11 140 patients with type 2 diabetes) analysis [19]. In ADVANCE, the recent use of statins was associated with a 55% (adjusted OR = 0.45, 95% CI 0.32 – 0.62) lower likelihood of presenting with an AMI than with stable angina [19]. In a recent study, short-term administration of atorvastatin (80 mg/day) in 304 patients with an eGFR < 60 ml/min/1.73 m² or placebo for 48 h before elective coronary angiography and/or angioplasty reduced the risk for AMI [20]. Multivariate analysis identified the pretreatment with high-dose atorvastatin as an independent predictor of reduced risk of AMI (OR = 0.39, 95% CI 0.16 – 0.96; p < 0.05) [20]. This rapid benefit indicates that statins protect from plaque rupture, mainly by pleiotropic effects.

Proximal location of coronary atherosclerotic lesions has been linked to the risk of AMI and to infarction-associated mortality [21]. A recent study showed that among 82 patients with stage 3 or higher CKD, atherosclerotic lesions were located closer to the coronary ostia, compared with 299 patients without CKD [21]. These data indicate that patients with CKD have more vulnerable plaques that are prone to rupture.

Virtual histology–intravascular ultrasound (VH-IVUS) provides coronary maps that are colour coded for four major plaque components in vivo [22]. Virtual histology analysis showed that patients on hemodialysis had a greater plaque volume, a lower percentage of fibrous plaque and a higher percentage of dense calcium plaque compared with controls that had normal renal function or mild renal impairment [22]. In addition, serum phosphate concentrations were significantly associated with the percentage of necrotic core in all study patients [22]. Therefore, plaque rupture in ESRD patients might be related to other risk factors, and this might explain why both atorvastatin and rosuvastatin did not show any clinical benefit (reduction in CVD morbidity or mortality) in ESRD patients in the 4D (atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis) and AURORA (a study to evaluate the use of rosuvastatin in subjects on regular hemodialysis) studies [23]. However, the SHARP (study of heart and renal protection) study [24] reported that the simvastatin + ezetimibe combination (compared with placebo) significantly reduced vascular events in predialysis and dialysed patients. SHARP may have been positive because of its size, which exceeds that of 4D and AURORA together.

Expert opinion

CKD patients (particularly those with an eGFR < 45 ml/min/1.73m2) are at higher risk of presenting with AMI compared with subjects with normal renal function, both in primary and secondary CVD prevention. Appropriate statins, at doses to achieve guideline goals, can ameliorate this risk in patients with CKD (up to stage 3). Treatment with statins should be initiated early (stage 3 CKD patients have not yet passed the point of no return) because in ESRD the contribution of statins in reducing the excessively high CVD morbidity or mortality may be limited [25].

The presence of stage 3 CKD is more closely related to AMI than to stable angina, because their plaques are more vulnerable, while in those with normal renal function the plaques tend to evolve towards reducing the coronary artery lumen. This difference is diminished by effective multifactorial treatment including a statin at an appropriate dose.

Declaration of interest

This editorial was written independently; no company or institution supported it financially. The authors have given talks, attended conferences and participated in trials and advisory boards sponsored by various pharmaceutical companies. VG Athyros and A Karagiannis have attended meetings sponsored by Pfizer, MSD and Astrazeneca. D Mikhailidis has attended meetings sponsored by Genzyme and MSD.