Atorvastatin in Patients with Type 2 Diabetes Mellitus Undergoing Dialysis
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《新英格兰医药杂志》
To the Editor: Wanner et al. (July 21 issue)1 report a lack of benefit from therapy with 20 mg of atorvastatin among patients with type 2 diabetes mellitus who were receiving hemodialysis, despite a high rate of cardiovascular events. In their discussion, the authors do not consider the possibility that this lack of benefit may have been related to a lack of appropriate exposure to statin therapy: approximately 50 percent of patients were no longer on the drug after two years of follow-up, and the rates for an average of four years of follow-up were not provided, though clearly even fewer patients would still have been receiving atorvastatin. In the 15 percent of patients who had a particularly good response to atorvastatin, with reductions in low-density lipoprotein (LDL) cholesterol levels to less than 1.3 mmol per liter (50 mg per deciliter), the dose was lowered. I would like to suggest that the lack of benefit in this important study was observed because only a minority of patients were exposed to the dose of 20 mg of atorvastatin throughout the duration of the study.
Anatoly Langer, M.D.
Canadian Heart Research Centre
Toronto, ON M5G 2P9, Canada
References
Wanner C, Krane V, M?rz W, et al. Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med 2005;353:238-248.
To the Editor: It would be erroneous to conclude from the German Diabetes and Dialysis Study that atorvastatin therapy does not benefit patients with diabetes who are receiving hemodialysis. In this study, half of the deaths from cardiac causes were classified as sudden. Statin therapy would not necessarily be expected to reduce the risk of arrhythmias attributable to hemodialysis; an analysis confined to the conventional cardiac end points of fatal and nonfatal myocardial infarction, death from coronary causes, and revascularization results in a relative risk of 0.81 (95 percent confidence interval, 0.57 to 0.94) in the atorvastatin group. Furthermore, it cannot be concluded that hemodialysis attenuates the benefit of atorvastatin therapy in patients with diabetes. In the Collaborative Atorvastatin Diabetes Study,1 the relative risk of these events was 0.56 (95 percent confidence interval, 0.41 to 0.80) with atorvastatin. The pathophysiological basis for the nonsignificant increase in fatal and nonfatal ischemic stroke in the study by Wanner et al. is unclear. However, 32 nonfatal and fatal cardiovascular events were still prevented with atorvastatin therapy. Since the safety of atorvastatin in patients receiving hemodialysis has been established, these patients should continue to be treated according to current guidelines for cardiovascular prevention.2,3
Jennifer G. Robinson, M.D., M.P.H.
University of Iowa
Iowa City, IA 52242
jennifer-g-robinson@uiowa.edu
Dr. Robinson reports having received speaker's fees and consulting fees from Pfizer and research grants from AstraZeneca, Bristol-Myers Squibb, Merck, Pfizer, and Sankyo.
References
Calhoun HM, Betteridge DJ, Durrington PN, et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet 2004;364:685-696.
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;285:2486-2498.
Kidney Disease Outcomes Quality Initiative (K/DOQI) Group. K/DOQI clinical practice guidelines for management of dyslipidemias in patients with kidney disease. Am J Kidney Dis 2003;41:Suppl 3:S1-S91.
To the Editor: Wanner et al. demonstrated that in patients with type 2 diabetes who had kidney failure and were receiving hemodialysis, atorvastatin therapy did not have a significant effect on the composite primary end point of death from cardiovascular causes, nonfatal myocardial infarction, and stroke. However, a doubling of the risk of fatal (primarily ischemic) stroke was observed among those receiving the drug. As the authors suggest, the lack of a beneficial effect on the composite primary end point might reflect the presence of advanced atherosclerosis and the involvement of nontraditional cardiovascular risk factors. However, composite outcomes present some challenges to interpretation,1 particularly when fatal and nonfatal outcomes are combined. The high risk of fatal stroke was both unexpected and unexplained, particularly in light of the results of the Collaborative Atorvastatin Diabetes Study. It is plausible that atorvastatin is beneficial only for the primary prevention of stroke. Since 18 percent of patients in the present study had preexisting cerebrovascular disease, a complementary approach would be to perform subgroup analyses comparing the risk of stroke among those with and those without the preexisting condition.
Bertrand L. Jaber, M.D.
Nicolaos E. Madias, M.D.
Caritas St. Elizabeth's Medical Center
Boston, MA 02135
bertrand_jaber@cchcs.org
References
Carneiro AV. Composite outcomes in clinical trials: uses and problems. Rev Port Cardiol 2003;22:1253-1263.
The authors reply: Dr. Langer notes a lack of exposure to statin therapy in study participants. There was high mortality among participants (49.2 percent mortality from all causes; median observation time, 4 years); 55 percent of patients were treated for more than 24 months with atorvastatin. Most discontinuations of treatment resulted from death or nonfatal myocardial infarction and stroke. Seventy-two percent of patients completed the course of study treatment according to protocol. The mean duration of atorvastatin exposure was 20 months in the 28 percent of subjects who discontinued treatment prematurely (i.e., those who reached an end point). Overall, the mean daily dose in all 619 atorvastatin patients was 19.3 mg. Therefore, we feel that this "lack of exposure" does not invalidate our findings. In fact, given the adherence to therapy and the LDL cholesterol level achieved with atorvastatin, we consider the atorvastatin exposure to have been sufficient.
Dr. Robinson believes that patients with type 2 diabetes who are undergoing hemodialysis should have continued to receive treatment according to current guidelines for cardiovascular prevention, a conclusion based on a post-specified subanalysis of the present study. We would note that the study was designed to detect a difference in the composite primary end point, including sudden death and stroke — not to show a reduction in the primary end point excluding sudden death and stroke. Since the analyses of the primary study end point demonstrated no significant difference, secondary end points are only nominally significant. The fact that we cannot explain the higher rate of ischemic stroke in the atorvastatin group does not mean that strokes did not occur. Consequently, safety issues remain on the agenda for future investigations. In the Assessment of Lescol in Renal Transplantation (ALERT) study, the relative risk of stroke was 1.16 (95 percent confidence interval, 0.83 to 1.63) with fluvastatin.1 We believe that extrapolating data from different patient populations, such as those in the Collaborative Atorvastatin Diabetes Study, is difficult.
Drs. Jaber and Madias discuss challenges in interpreting composite end points, and they request subgroup analyses. We would advise caution with regard to the subsequent interpretation of data originating from very small groups, and we point out that among patients without prior cerebrovascular disease, fatal strokes occurred in 8 who were receiving placebo and 20 who were receiving atorvastatin (relative risk, 2.32; 95 percent confidence interval, 1.02 to 5.29; P=0.045). In contrast, no difference was evident among those with prior cerebrovascular disease. Adjustment for preexisting cerebrovascular disease in the multivariate Cox regression analysis showed similar results (relative risk, 2.08; 95 percent confidence interval, 1.07 to 4.04). Thus, on the basis of previous data and treatment decisions, it seems reasonable to combine both cerebrovascular and cardiovascular morbidity and mortality.
Christoph Wanner, M.D.
Vera Krane, M.D.
Hospital of the Bavarian Julius-Maximilians University
97080 Wurzburg, Germany
wanner_c@medizin.uni-wuerzburg.de
Eberhard Ritz, M.D.
Ruperto Carola University Hospital
69115 Heidelberg, Germany
Since publication of his article, Dr. Wanner reports having received lecture fees from Pfizer.
References
Holdaas H, Fellstr?m B, Jardine AG, et al. Effect of fluvastatin on cardiac outcomes in renal transplantation recipients: a multicentre, randomised, placebo-controlled trial. Lancet 2003;361:2024-2031.
Anatoly Langer, M.D.
Canadian Heart Research Centre
Toronto, ON M5G 2P9, Canada
References
Wanner C, Krane V, M?rz W, et al. Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med 2005;353:238-248.
To the Editor: It would be erroneous to conclude from the German Diabetes and Dialysis Study that atorvastatin therapy does not benefit patients with diabetes who are receiving hemodialysis. In this study, half of the deaths from cardiac causes were classified as sudden. Statin therapy would not necessarily be expected to reduce the risk of arrhythmias attributable to hemodialysis; an analysis confined to the conventional cardiac end points of fatal and nonfatal myocardial infarction, death from coronary causes, and revascularization results in a relative risk of 0.81 (95 percent confidence interval, 0.57 to 0.94) in the atorvastatin group. Furthermore, it cannot be concluded that hemodialysis attenuates the benefit of atorvastatin therapy in patients with diabetes. In the Collaborative Atorvastatin Diabetes Study,1 the relative risk of these events was 0.56 (95 percent confidence interval, 0.41 to 0.80) with atorvastatin. The pathophysiological basis for the nonsignificant increase in fatal and nonfatal ischemic stroke in the study by Wanner et al. is unclear. However, 32 nonfatal and fatal cardiovascular events were still prevented with atorvastatin therapy. Since the safety of atorvastatin in patients receiving hemodialysis has been established, these patients should continue to be treated according to current guidelines for cardiovascular prevention.2,3
Jennifer G. Robinson, M.D., M.P.H.
University of Iowa
Iowa City, IA 52242
jennifer-g-robinson@uiowa.edu
Dr. Robinson reports having received speaker's fees and consulting fees from Pfizer and research grants from AstraZeneca, Bristol-Myers Squibb, Merck, Pfizer, and Sankyo.
References
Calhoun HM, Betteridge DJ, Durrington PN, et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet 2004;364:685-696.
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;285:2486-2498.
Kidney Disease Outcomes Quality Initiative (K/DOQI) Group. K/DOQI clinical practice guidelines for management of dyslipidemias in patients with kidney disease. Am J Kidney Dis 2003;41:Suppl 3:S1-S91.
To the Editor: Wanner et al. demonstrated that in patients with type 2 diabetes who had kidney failure and were receiving hemodialysis, atorvastatin therapy did not have a significant effect on the composite primary end point of death from cardiovascular causes, nonfatal myocardial infarction, and stroke. However, a doubling of the risk of fatal (primarily ischemic) stroke was observed among those receiving the drug. As the authors suggest, the lack of a beneficial effect on the composite primary end point might reflect the presence of advanced atherosclerosis and the involvement of nontraditional cardiovascular risk factors. However, composite outcomes present some challenges to interpretation,1 particularly when fatal and nonfatal outcomes are combined. The high risk of fatal stroke was both unexpected and unexplained, particularly in light of the results of the Collaborative Atorvastatin Diabetes Study. It is plausible that atorvastatin is beneficial only for the primary prevention of stroke. Since 18 percent of patients in the present study had preexisting cerebrovascular disease, a complementary approach would be to perform subgroup analyses comparing the risk of stroke among those with and those without the preexisting condition.
Bertrand L. Jaber, M.D.
Nicolaos E. Madias, M.D.
Caritas St. Elizabeth's Medical Center
Boston, MA 02135
bertrand_jaber@cchcs.org
References
Carneiro AV. Composite outcomes in clinical trials: uses and problems. Rev Port Cardiol 2003;22:1253-1263.
The authors reply: Dr. Langer notes a lack of exposure to statin therapy in study participants. There was high mortality among participants (49.2 percent mortality from all causes; median observation time, 4 years); 55 percent of patients were treated for more than 24 months with atorvastatin. Most discontinuations of treatment resulted from death or nonfatal myocardial infarction and stroke. Seventy-two percent of patients completed the course of study treatment according to protocol. The mean duration of atorvastatin exposure was 20 months in the 28 percent of subjects who discontinued treatment prematurely (i.e., those who reached an end point). Overall, the mean daily dose in all 619 atorvastatin patients was 19.3 mg. Therefore, we feel that this "lack of exposure" does not invalidate our findings. In fact, given the adherence to therapy and the LDL cholesterol level achieved with atorvastatin, we consider the atorvastatin exposure to have been sufficient.
Dr. Robinson believes that patients with type 2 diabetes who are undergoing hemodialysis should have continued to receive treatment according to current guidelines for cardiovascular prevention, a conclusion based on a post-specified subanalysis of the present study. We would note that the study was designed to detect a difference in the composite primary end point, including sudden death and stroke — not to show a reduction in the primary end point excluding sudden death and stroke. Since the analyses of the primary study end point demonstrated no significant difference, secondary end points are only nominally significant. The fact that we cannot explain the higher rate of ischemic stroke in the atorvastatin group does not mean that strokes did not occur. Consequently, safety issues remain on the agenda for future investigations. In the Assessment of Lescol in Renal Transplantation (ALERT) study, the relative risk of stroke was 1.16 (95 percent confidence interval, 0.83 to 1.63) with fluvastatin.1 We believe that extrapolating data from different patient populations, such as those in the Collaborative Atorvastatin Diabetes Study, is difficult.
Drs. Jaber and Madias discuss challenges in interpreting composite end points, and they request subgroup analyses. We would advise caution with regard to the subsequent interpretation of data originating from very small groups, and we point out that among patients without prior cerebrovascular disease, fatal strokes occurred in 8 who were receiving placebo and 20 who were receiving atorvastatin (relative risk, 2.32; 95 percent confidence interval, 1.02 to 5.29; P=0.045). In contrast, no difference was evident among those with prior cerebrovascular disease. Adjustment for preexisting cerebrovascular disease in the multivariate Cox regression analysis showed similar results (relative risk, 2.08; 95 percent confidence interval, 1.07 to 4.04). Thus, on the basis of previous data and treatment decisions, it seems reasonable to combine both cerebrovascular and cardiovascular morbidity and mortality.
Christoph Wanner, M.D.
Vera Krane, M.D.
Hospital of the Bavarian Julius-Maximilians University
97080 Wurzburg, Germany
wanner_c@medizin.uni-wuerzburg.de
Eberhard Ritz, M.D.
Ruperto Carola University Hospital
69115 Heidelberg, Germany
Since publication of his article, Dr. Wanner reports having received lecture fees from Pfizer.
References
Holdaas H, Fellstr?m B, Jardine AG, et al. Effect of fluvastatin on cardiac outcomes in renal transplantation recipients: a multicentre, randomised, placebo-controlled trial. Lancet 2003;361:2024-2031.