NDT Advance Access originally published online on July 22, 2008
Nephrology Dialysis Transplantation 2008 23(10):3370-3371; doi:10.1093/ndt/gfn389
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Optimal TARGETs for cardiovascular safety and benefit in ESRD
Nephrol Dial Transplant 2008; doi:10.1093/ndt/gfn425E-mail: dsane{at}wfubmc.edu
Sir,
The TARGET investigators recently reported their study of combined calcimimetic (cinacalcet) and low-dose vitamin D sterol therapy in patients with end-stage renal disease (ESRD) and moderate-to-severe secondary hyperparathyroidism [1]. KDOQI chronic kidney disease bone and mineral disorder (CKD-MBD) biochemical targets for parathyroid hormone (PTH) and calcium–phosphate product (Ca x P) were achieved in 54% of patients with cinacalcet and vitamin D sterol dosing equivalent to paricalcitol 10 mcg per week. While we appreciate the efforts to improve metabolic control in this patient population, we are concerned about the significant rates of hypocalcaemia, which occurred because cinacalcet was titrated, while vitamin D sterol use was limited. We are also concerned about the lack of cardiovascular safety monitoring and have reservations about the general cardiovascular implications of this strategy. The incidence of hypocalcaemia ranged from 9% (using the stringent criterion of two serum calcium values <7.5 mg/dl) to 78% using the cut point of a single calcium value of <8.4 mg/dl. Hypocalcaemia prolongs the QT interval, which increases the propensity for ventricular arrhythmias and sudden cardiac death, especially in the presence of structural heart disease. Since haemodialysis itself increases the QT interval and QT dispersion [2] and because sudden cardiac death is common in ESRD patients, hypocalcaemia is not necessarily a benign laboratory abnormality. The TARGET trial excluded patients with prior myocardial infarction (MI) or recent unstable medical conditions. In clinical practice, at least 40% of patients with ESRD have prevalent cardiovascular disease, and patients on dialysis have a 30-fold higher cardiovascular disease-associated mortality than the general population [3]. Dialysis patients with MI have a twofold higher rate of cardiac arrest compared to non-dialysis patients with MI [4]. We are concerned that no data on EKG findings (especially the QT interval) or telemetry monitoring were reported by the TARGET investigators. It would be helpful to know the serum calcium levels of the nine patients who died, and whether they succumbed to an arrhythmic event. Hypocalcaemia also reduces myocardial contractility, an effect that could exacerbate the high rates of heart failure in ESRD patients. Finally, vitamin D sterol therapy has a variety of ‘non-classical’ effects, including inhibition of the renin–angiotensin–aldosterone system and anti-inflammatory and anticoagulant effects that are not shared by cinacalcet [5]. Accordingly, PTH and Ca x P product may not be optimal biomarkers for assessing the potential cardiovascular benefits or risks of strategies designed to meet the CKD-MBD targets. We suggest that the QT interval, brain natriuretic peptide, plasminogen activator inhibitor-1, C-reactive protein, angiotensin II and aldosterone levels would be more appropriate surrogate markers for evaluating cardiovascular risk and benefit in future trials of vitamin D sterols, cinacalcet or combination therapy.
Conflict of interest statement. The author has received honoraria for speaking at symposia sponsored by Abbott, manufacturer to paricalcitol.
Internal Medicine/Cardiology Wake Forest University Health Sciences, Winston-Salem, NC, USA
References
- Block GA, Zeig S, Sugihara J, et al. Combined therapy with cinacalcet and low dose of vitamin D sterols in patients with moderate to severe secondary hyperparathyroidism. Nephrol Dial Transplant (2008) 1–8.
- Selby NM, McIntyre CW. The acute cardiac effects of dialysis. Semin Dial (2007) 20:220–228.[CrossRef][Web of Science][Medline]
- Levey AS, Beta JA, Coronado BE, et al. Controlling the epidemic of cardiovascular disease in chronic renal disease: what do we know? What do we need to learn? Where do we go from here? National Kidney Foundation Task Force on Cardiovascular Disease. Am J Kidney Dis (1998) 32:853–906.[Web of Science][Medline]
- Herzog CA, Littrell K, Arko C, et al. Clinical characteristics of dialysis patients with acute myocardial infarction in the United States: a collaborative project of the United States Renal Data System and the National Registry of Myocardial Infarction. Circulation (2007) 116:1465–1472.
[Abstract/Free Full Text] - Andress D. Nonclassical aspects of differential vitamin D receptor activation: implications for survival in patients with chronic kidney disease. Drugs (2007) 67:199–2012.
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