The direction of our data suggests that coronary artery calcification may predict death, although this did not reach statistical significance. Additionally, there were tendencies towards association with future myocardial infarction, total events and event-free survival. Our findings suggest an increased risk of CV events, CV death, and death from all causes associated with having a higher coronary calcification score. When adjusted for age, the hazard ratio decreases from 2.5 (95 % CI 0.87, 7.3) to 1.7 (95 % CI 0.55, 5.4), suggesting that age may be a confounder.
Our results are consistent with one prospective study of 103 patients on HD with a follow up of 44 months that demonstrated a tendency towards increased relative risk for death of 2.7 (95 % CI 0.9, 8.3) for patients on hemodialysis having coronary calcification scores above 200 compared to those with scores below 200 (p = 0.08) [11]. Similarly, another prospective study examining 56 prevalent patients on HD over 15 months [8] found that patients with coronary calcification scores above the median had a relative risk for cardiovascular events of 2.6 (95 % CI 1.2, 5.5; p = 0.01), a relative risk for cardiovascular death of 3.1 (95 % CI 0.7, 14.3; p = 0.14), and a relative risk for death from all causes of 3.3 (95 % CI 1.4, 7.8; p = 0.007) [8]. However, this study used a composite for cardiovascular events that consisted of a heterogeneous mix of hard and soft outcomes including angina, myocardial infarction, percutaneous coronary intervention, CABG, severe valve disease, heart failure, and stroke [8]. In a 24-month prospective study of 117 patients with CKD who were not on HD, patients with coronary calcification scores ≥ 400 had an increased risk of cardiovascular events (a heterogeneous cluster of acute myocardial infarction, stroke, angina, arrhythmia, uncontrolled hypertension and cardiac failure) (HR = 3.53; 95 % CI: 1.03, 12.06; p = 0.04), and hospitalizations (HR = 4.05; 95 % CI 1.4, 11.5; p = 0.009) [12]. Cox regression was not conducted for deaths as there were no deaths in patients with coronary calcification scores < 400 compared with 4 in the group ≥ 400 (p = 0.002) [12]. Another study of 64 patients with ESRD on maintenance HD followed for 18 months found, in its secondary analysis, that cardiovascular outcomes occurred in 35 % of patients with a coronary calcification score > 10 compared, and in 0 % of patients with a coronary calcification score < 10 [10]. Patients who experienced a cardiovascular event had a higher mean coronary calcification score (1017 SD 975) than those who had not (129 SD 336) (p = 0.02) [10]. As in other studies, the cardiovascular outcome composite included both hard and soft outcomes (new-onset angina, myocardial infarction, angioplasty, and coronary artery bypass surgery) [10]. Another prospective study in 127 incident patients on HD followed for 18 months found a mean baseline coronary calcification score of 391 (SD 693) in patients alive at the end of the study and 1373 (SD 2034) in the 34 patients who had died (p <0.0001) [13]. Cardiovascular outcomes and risk were not reported [13].
One previous investigation of incident patients on HD reported a proportional increase in mortality with increasing coronary calcification, but did not report cardiovascular outcomes [14, 15]. This study, a clinical trial investigating the effect of the non-calcium phosphate binder sevalamer hydrochloride compared with calcium-containing phosphate binders on progression of coronary artery calcification in patients new to hemodialysis, observed progression of CAC in patients with baseline CAC >30, and that patients who were randomized to calcium-containing phosphate binders had a more rapid rate of progression that those randomized to sevalamer (p = 0.056 at 12 months; p = 0.01 at 18 months) [14].
Coronary calcification above the median was associated with older age, higher alkaline phosphatase, and higher hemoglobin, and a tendency toward a higher prevalence of diabetes as cause of ESRD (but not a higher prevalence of current diabetes). No differences were seen in serum calcium, phosphorus, calcium-phosphate product, iPTH, urea reduction ratio, or current warfarin use. Cross-sectional studies and baseline associations have shown consistent correlations between coronary calcification score and age [9, 11, 13, 18], duration of diabetes [6], HD vintage [7–9, 11], alkaline phosphatase [7], and fetuin-A [9]. Associations have been inconsistent for coronary calcification score and serum intact PTH [9, 10, 13], C-reactive protein [7, 9, 10, 13], serum calcium [7, 9, 18], serum creatinine [7, 13], cholesterol [7, 18], diabetes [7, 11, 18], smoking [7, 18], and hypertension [11, 18].
This study is one of the few that has looked at coronary artery calcification in incident ESRD, and is the only one, to our knowledge, that has prospectively examined both cardiovascular outcomes and death in this population. Much of the prior evidence has been derived from prevalent patients on maintenance HD [7–11, 18]. We had a well-characterized population at baseline, with an a priori decision to group patients on the basis of having a coronary calcification score above and below the median. Our composite outcome was a homogenous event cluster of serious, adjudicated cardiovascular events (stroke, MI), cardiovascular death, and death from all causes. We learned that patients at this stage of illness are very much deterred by the respondent burden of testing that requires an additional appointment. We were limited by a small sample size and a small number of events and thus, we were limited in the ability to perform multivariable adjustments. The small sample size may have led to type II error in the absence of association between biochemical markers, baseline clinical status and cardiac calcification. Patients who consented to this calcification substudy were younger than those in the study as a whole, and though this should not threaten the internal validity of the findings, it is a reminder of the challenges of observational studies with substantial respondent burden (such as the additional visit and risk associated with CT in this study) in patients already heavily burdened by an intrusive disease and an intrusive treatment.