Correspondence

Rosuvastatin in Patients Undergoing Hemodialysis

N Engl J Med 2009; 361:93-95July 2, 2009

Article

To the Editor:

In their article on A Study to Evaluate the Use of Rosuvastatin in Subjects on Regular Hemodialysis: An Assessment of Survival and Cardiovascular Events (AURORA), Fellström et al. (April 2 issue)1 report little benefit for rosuvastatin in reducing the rates of cardiovascular events and death in patients undergoing hemodialysis. This distinction from the effect in the general population is primarily because the cause of cardiovascular disease in patients undergoing hemodialysis is multifactorial and goes beyond the traditional atherothrombotic mechanisms. Therefore, any study of the use of statins should elaborate on the extent of control of hyperphosphatemia2 and hyperparathyroidism,2 which affect vascular calcification, and the incidence of hyperhomocysteinemia3 in study patients. In AURORA, the baseline serum phosphorus level of 1.8 mmol per liter (5.6 mg per deciliter) corresponds to the third quintile in the United States Renal Data System study (waves 1, 3, and 4), which showed an already elevated baseline risk (1.13) for adverse cardiovascular events. Similarly, data on the incidence of left ventricular hypertrophy, a powerful predictor of cardiovascular events in patients undergoing hemodialysis,4 is missing from AURORA. Given the formidable task of adjusting for so many confounding factors, it is premature to write off the role of statins in protection against cardiovascular disease in patients undergoing hemodialysis.

Anirban Ganguli, M.D.
INSCOL Hospital, Chandigarh 160034, India
ranaganguli19782003@yahoo.co.in

4 References

1
Fellstrom BC, Jardine AG, Schmieder RE, et al. Rosuvastatin and cardiovascular events in patients undergoing hemodialysis. N Engl J Med 2009;360:1395-1407
Full Text | Web of Science | Medline

2
Slinin Y, Foley RN, Collins AJ. Calcium, phosphorus, parathyroid hormone, and cardiovascular disease in hemodialysis patients: the USRDS Waves 1, 3, and 4 Study. J Am Soc Nephrol 2005;16:1788-1793
CrossRef | Web of Science | Medline

3
Mallamaci F, Zoccali C, Tripepi G, et al. Hyperhomocysteinemia predicts cardiovascular outcomes in hemodialysis patients. Kidney Int 2002;61:609-614
CrossRef | Web of Science | Medline

4
Zoccali C, Benedetto F, Mallamaci F, et al. Left ventricular mass monitoring in the follow-up of dialysis patients: prognostic value of left ventricular hypertrophy progression. Kidney Int 2004;65:1492-1498
CrossRef | Web of Science | Medline

To the Editor:

There are two factors that might explain why AURORA did not show a cardiovascular benefit for rosuvastatin in dialysis patients. First, there was an almost statistically significant predominance of patients with diabetes (P=0.06) or diabetic nephropathy as the cause of end-stage renal disease (P=0.08) in the rosuvastatin group. Since diabetes is an independent cardiovascular risk factor and statins do not confer any cardiovascular benefit in dialysis patients with diabetes (as shown in the German Diabetes and Dialysis Study1), this imbalance in AURORA may have masked a beneficial effect of statins in the overall dialysis population. Second, it is known that cardiovascular mortality increases progressively through the early stages of chronic kidney disease and becomes very high in dialysis patients (10 to 30 times as high as that in the general population).2 Therefore, it might be too late for statins to provide any benefit in patients with such a high risk of death from cardiovascular causes. Conversely, given the evidence suggesting a benefit for statins in predialysis chronic kidney disease,3,4 the forthcoming results of Study of Heart and Renal Protection (SHARP) and the Prospective Evaluation of Proteinuria and Renal Function in Diabetic Patients with Progressive Renal Disease Trial (PLANET) may provide good news about statins in patients with chronic kidney disease not requiring dialysis.

Theodoros I. Kassimatis, M.D., Ph.D.
Evangelismos General Hospital, 10676 Athens, Greece

Panagiotis A. Konstantinopoulos, M.D., Ph.D.
Beth Israel Deaconess Medical Center, Boston, MA 02215
pkonstan@bidmc.harvard.edu

4 References

1
Wanner C, Krane V, Marz W, et al. Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med 2005;353:238-248[Erratum, N Engl J Med 2005;353:1640.]
Full Text | Web of Science | Medline

2
Sarnak MJ, Levey AS, Schoolwerth AC, et al. Kidney disease as a risk factor for development of cardiovascular disease: a statement from the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention. Circulation 2003;108:2154-2169
CrossRef | Web of Science | Medline

3
Kassimatis TI, Konstantinopoulos PA. The role of statins in chronic kidney disease (CKD): friend or foe? Pharmacol Ther 2009;122:312-323
CrossRef | Web of Science | Medline

4
Navaneethan SD, Pansini F, Perkovic V, et al. HMG CoA reductase inhibitors (statins) for people with chronic kidney disease not requiring dialysis. Cochrane Database Syst Rev 2009;2:CD007784-CD007784
Medline

To the Editor:

AURORA showed no benefit of rosuvastatin in patients with end-stage renal disease undergoing hemodialysis. Conversely, in the Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER),1 which evaluated the same statin in a much larger and healthier population, there was a significant benefit in all cardiovascular end points and total mortality.

It is possible that the devastating effects of hypertension, diabetes, dyslipidemia, and chronic inflammation long before and during end-stage renal disease may mitigate any benefit associated with statins. One other plausible explanation for this great discrepancy of statin effects in people with and without end-stage renal disease is the effect of inadequate dialysis. Large observational studies have shown that the vast majority of patients with end-stage renal disease were undertreated for many important cardiovascular risk factors, such as chronic hypervolemia and hypertension.2,3 Prospective, randomized clinical trials that compare not only the hemodialysis regimen but also treatment times and methods are urgently needed4 before statins are considered to be useless drugs in patients with end-stage renal disease who are undergoing hemodialysis.

Jose Mario F. de Oliveira, M.D., Ph.D.
Universidade Federal Fluminense, 24230-030 Niteroi, Brazil
jmariofranco@gmail.com

Dr. de Oliveira reports being an owner of and serving as a staff nephrologist for Clinica DERT, a private, for-profit dialysis unit. No other potential conflict of interest relevant to this letter was reported.

4 References

1
Ridker PM, Danielson E, Fonseca FAH, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008;359:2195-2207
Full Text | Web of Science | Medline

2
Kalantar-Zadech K, Regidor DL, Kovesdy CD, et al. Fluid retention is associated with cardiovascular mortality in patients undergoing long-term hemodialysis. Circulation 2009;119:671-679
CrossRef | Web of Science | Medline

3
Charra B, Calemard E, Lauren G. Importance of treatment time and blood pressure control in achieving long-term survival on dialysis. Am J Nephrol 1996;16:35-44
CrossRef | Web of Science | Medline

4
Scribner BH. Medical dilemmas: when the old is new. Nat Med 2002;8:1066-1067
CrossRef | Web of Science | Medline

Author/Editor Response

The pathogenesis of cardiovascular events in patients undergoing hemodialysis is multifactorial, involving calcification, inflammation, and dyslipidemia, although hyperlipidemia is not a risk factor. In our study, we could not demonstrate a beneficial effect of cholesterol reduction with statin therapy in patients undergoing hemodialysis. This may reflect the lack of association between cholesterol levels and cardiovascular events, but as the correspondents suggest, there may be additional limitations of the study.

Diabetes was the cause of renal failure in 19% of the patients in our study. Diabetes is one of the strongest risk factors for cardiovascular disease in patients with chronic kidney disease; this was also the case in our study. There was a trend toward a treatment benefit for rosuvastatin among patients with diabetes, although the difference in the primary outcome of death from cardiovascular causes, nonfatal stroke, or nonfatal myocardial infarction was not statistically significant.

Hyperphosphatemia is an important risk factor contributing to vascular calcification and is not treatable with statins. In our study, a high phosphate level was one of the strongest risk factors for the occurrence of cardiovascular end points. (These results were presented at the World Congress of Nephrology in Milan on May 23, 2009.)

Another important risk factor is inflammation. Levels of high-sensitivity C-reactive protein (hsCRP) were elevated (5 mg per liter) in both study groups, and there was a reduction of 11% from baseline in the group receiving 10 mg of rosuvastatin, whereas the level remained increased in the placebo group. However, the reduction in the rosuvastatin group was less than that in JUPITER (ClinicalTrials.gov number, NCT00239681), and the achieved median levels were higher. Increased baseline hsCRP levels were associated with a risk of major cardiovascular events in our study. It is possible that the lack of a reduction in the rate of cardiovascular events may have been at least partially a consequence of the limited reduction in hsCRP, which in turn may have been a consequence of the causes of elevated hsCRP in this population, including the hemodialysis procedure used rather than inflammation within the atherosclerotic plaque.

The time point for starting treatment may also be important. In our study, only patients over 50 years of age were included. It is possible that younger patients who start statin treatment at an earlier point (e.g., during stages 2 to 4 of chronic kidney disease) might benefit from statin treatment. However, starting treatment with a statin in patients who are over the age of 50 years and who have been undergoing dialysis for 3 to 4 years is not beneficial, probably because the deleterious vascular consequences of dialysis are irreversible by this stage.

Bengt Fellström, M.D., Ph.D.
University Hospital, 75185 Uppsala, Sweden
bengt.fellstrom@medsci.uu.se

Alan Jardine, M.D.
BHF Glasgow Cardiovascular Research Centre, Glasgow G12 8TA, United Kingdom

Hallvard Holdaas, M.D., Ph.D.
Oslo University Hospital, N-0072 Oslo, Norway

for the AURORA Executive Steering Committee

Citing Articles (2)

Citing Articles

1
Theodoros I. Kassimatis, Athanasios Agrafiotis. (2010) Chronic kidney disease: Implications of the AURORA and JUPITER results. Nature Reviews Nephrology 6:11, 636-637
CrossRef
2
Theodoros I. Kassimatis, David J.A. Goldsmith. (2010) New Hope for Chronic Kidney Disease Patients After the JUPITER Trial. Journal of the American College of Cardiology 56:6, 529
CrossRef