CARDIOLOGY REPORTTM. Evaluation of Fluvastatin in Renal Transplant Recipients: The ALERT Trial

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1 Volume 1, Number 1 Fall 2003 The CARDIOLOGY REPORTTM AN ACADEMIC PERSPECTIVE Evaluation of Fluvastatin in Renal Transplant Recipients: The ALERT Trial A report on the Assessment of LEscol in Renal Transplantation (ALERT) trial, as presented at the American Transplant Congress 2003 Darshana Dadhania, MD Transplant Medicine Fellow, Division of Nephrology Weill Medical College of Cornell University, New York, New York With an introduction by Antonio M. Gotto, Jr., MD, DPhil The Stephen and Suzanne Weiss Dean and Professor of Medicine Weill Medical College of Cornell University, New York, New York Supported by an unrestricted educational grant from Reliant Pharmaceuticals, LLC

2 Guest Editor: Antonio M. Gotto, Jr., MD, DPhil The opinions or views expressed in this publication are those of the authors and do not necessarily reflect the opinions or recommendations of Reliant Pharmaceuticals, LLC, or the publisher, Direct One Communications, Inc. Please consult the full prescribing information before using any medication mentioned in this publication. This educational publication was made possible through an unrestricted educational grant from Reliant Pharmaceuticals, LLC. Copyright 2003 by Direct One Communications, Inc. All rights reserved. Printed in the USA.

3 Introduction Treating High-Risk Patients With Statin Therapy Antonio M. Gotto, Jr., MD, DPhil Weill Medical College of Cornell University, New York, New York Statins (3-hydroxy-3-methylglutaryl coenzyme A [HMG-CoA] reductase inhibitors) are at the forefront of lipid-modifying drug therapies. This is largely because of the substantial and consis- tent clinical trial database that shows that agents of this drug class reduce the risk for cardiovascular disease in a broad range of at-risk patients. The first landmark clinical trial of statins, the Scandinavian Simvastatin Survival Study, 1 showed the value of these drugs in patients at highest risk those who had coronary heart disease (CHD) and highly elevated cholesterol levels. This study was the first to show that treatment with a statin could reduce not only coronary morbidity and mortality but also all-cause mortality. Since then, several investigators have reported that statins also reduce coronary risk in patients with or without CHD who have elevated or average levels of low-density lipoprotein cholesterol or below-average levels of protective high-density lipoprotein cholesterol. At the same time, there has been a growing appreciation of the synergistic effects of having multiple coronary risk factors. Guidelines have shifted the focus away from the isolated evaluation and management of individual risk factors to the consideration of the total risk profile (so-called global risk assessment). This transition in philosophy has also influenced the design of studies. The most recent clinical endpoint trials of statins have randomized patients not on the basis of having lipid disorders per se but on the basis of being at risk for cardiovascular disease in the near term. These trials have included patients with or without CHD who are at risk for other cardiovascular diseases, as well as those with diabetes 2 or hypertension 3 and the elderly. 4 CHD-Risk Equivalent The third National Cholesterol Education Program Adult Treatment Panel (ATP III) guidelines combine lipid measurement with global risk assessment to make recommendations for dietary or pharmacologic therapy. 5 The ATP III delineates three major at-risk groups that require treatment at varying degrees of intensity: patients with CHD or with a riskfactor profile equivalent to having CHD; those without CHD but who have two or more risk factors; and those without CHD but who have no or only one risk factor. The identific a- tion of a CHD-risk equivalent group is an important new feature Dr. Gotto is the Stephen and Suzanne Weiss Dean and Professor of Medicine, Weill Medical College of Cornell University, New York, New York. of US guidelines. Included in this category are patients who have other forms of vascular disease (such as peripheral or cerebrovascular disease or aortic aneurysm), those with diabetes, and those with a 10-year risk for CHD greater than 20%. Although not mentioned in ATP III, a case could be made to include the presence of endstage renal disease as another CHD equivalent profile, given the markedly higher rate of CHD in these patients compared with that in the general population. The findings of the Assessment of LEscol in Renal Transplantation (ALERT) trial discussed in the following summary by Dr. Darshana Dadhania provide interesting information about the possible effects of statin treatment in renal transplantation patients. 6 The association between renal disease and increased risk for CHD is well established, perhaps explained in part by the dyslipidemia and enhanced oxidative stress present in endstage renal disease. Transplantation also may accelerate atherogenesis, and statin treatment has improved survival and dyslipidemia in small studies of heart transplantation patients. 7 1

4 Antonio M. Gotto, Jr., MD, DPhil Although the ALERT trial did not show a significant reduction in the primary endpoint of major adverse cardiac events, the secondary reduction in coronary events with fluvastatin represents an important contribution to our knowledge about CHD prevention in this patient group. This finding is sure to stimulate future research that will continue to elucidate the potential applications of the statins. Probing the boundaries of these applications may improve recommendations for the optimal use of available therapies and help identify novel targets for investigation. References 1. Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344: Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002;360: Sever PS, Dahlof B, Poulter NR, et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet. 2003;361: Shepherd J, Blauw GJ, Murphy MB, et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet. 2002;360: Expert Panel on the 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: Holdaas H, Fellstrom B, Jardine AG, et al. Effect of fluvastatin on cardiac outcomes in renal transplant recipients: a multicentre, randomised, placebo-controlled trial. Lancet. 2003;361: Kobashigawa JA, Katznelson S, Laks H, et al. Effect of pravastatin on outcomes after cardiac transplantation. N Engl J Med. 1995;333:

5 Evaluation of Fluvastatin in Renal Transplant Recipients: The ALERT Trial Darshana Dadhania, MD Weill Medical College of Cornell University, New York, New York Most renal transplant recipients already have one or more cardiovascular risk factors prior to kidney transplantation, and they acquire additional risk factors following transplantation. More than one half of all renal transplant patients have hyperlipidemia. By lowering lipid levels, statins may improve patient outcome following renal transplantation and reduce cardiovascular mortality. The first large-scale, multicenter study among renal transplant patients found that fluvastatin safely lowered total cholesterol and low-density lipoprotein-cholesterol levels in this patient population. Holdaas and colleagues reported a 17% reduction in the occurrence of major adverse cardiac events (P = 0.139), the primary endpoint of this randomized, double-blind, placebo-controlled trial. Fluvastatin also had a statistically significant impact on some secondary endpoints, reducing the combined incidence of cardiac mortality and nonfatal myocardial infarction (P = 0.005). All-cause mortality and the renal composite endpoint of graft loss or doubling of serum creatinine levels were similar in the fluvastatin and placebo treatment groups. Unlike other statins, fluvastatin has a minimal risk for drug-drug interaction with cyclosporine. The study discussed in this paper, with all patients receiving cyclosporine, found no increase in adverse effects in the fluvastatin-treated group, expanding the safety database for fluva statin to the renal transplant population. Many patients who undergo renal transplant survive the procedure and aftermath, only to die later from cardiovascular events. Renal transplant patients are far more likely to die from accelerated premature cardiovascular disease than from renal failure. Analysis of the United Network for Organ Sharing (UNOS) registry revealed that cardiovascular events were responsible for 35% to 40% of deaths among renal transplant patients who died with a functioning graft, more than double the percentage of deaths due to infection or sepsis. 1 3 The effects of impaired renal function, proteinuria, ongoing inflammation, and immunosuppressive medications may make renal transplant recipients more susceptible to certain cardiovascular disease risk factors. These factors include hypercholesterolemia, hypertension, diabetes, and hyperhomocysteinemia. 4,5 In addition to the increased risks associated with their status as transplant recipients, these patients may also have risks related to smoking, obesity, age, gender, and genetic background. As a result, modifying cardiovascular risk factors may be particularly useful in renal transplant recipients. Lipid Disorders Are Prevalent Dr. Dadhania is a Transplant Medicine Fellow, Division of Nephrology, Weill Medical College of Cornell University, New York, New York. Lipid disorders are more frequent in renal transplant recipients compared with the general population (Table 1). About 60% of renal transplant recipients have a total cholesterol level > 240 mg/dl and a low-density lipoprotein (LDL)-cholesterol level > 130 mg/dl. A significant proportion of these patients also has increased triglyceride and lipoprotein (a) serum levels. 6 T h e r i s k f o r ischemic heart disease associated with hypercholesterolemia appears to be greater in renal transplant recipients than in the general population. 5 An association between 3

6 Darshana Dadhania, MD Table 1 Lipid Abnormalities in the General Population and in Renal Transplant Recipients General Renal transplant Lipid abnormality population recipients Total cholesterol > 240 mg/dl (6.2 mmol/l) 20% 60% LDL-cholesterol > 130 mg/dl (3.4 mmol/l) 40% 60% HDL-cholesterol < 35 mg/dl (0.9 mmol/l) 15% 15% Triglycerides > 200 mg/dl (5.2 mmol/l) 15% 35% Lipoprotein (a) > 30 mg/dl (0.78 mmol/l) 15% 25% Adapted from Kasiske 6 increased cholesterol and poor allograft function has also been reported. Renal transplant recipients with high total cholesterol levels have lower creatinine clearance 7 and higher rates of graft failure 1 year posttransplantation. In addition to short-term graft loss, hyperlipidemia is considered a risk factor for chronic allograft nephropathy, hyperplasia, and proliferation of the vascular intima. 8 Impact of Immunosuppressants Immunosuppressive agents contribute to the increased incidence of hyperlipidemia in renal transplant recipients. Although cyclosporine is widely acknowledged as having revolutionized immunosuppressive therapy for renal transplant patients, it has been shown to increase both total cholesterol and LDL-cholesterol levels. 9 Corticosteroids have been shown to increase total cholesterol and, specifically, very low-density lipoprotein (VLDL)-cholesterol and high-density lipoprotein (HDL)-cholesterol levels in healthy individuals. 10,11 Withdrawal of corticosteroids decreases total cholesterol levels in renal transplant patients whose baseline immunosuppressive therapy consisted of cyclosporine, azathioprine, and prednisone. 12 Calcineurin inhibitors have also been implicated in the enhanced oxidation of LDL, a process implicated in the initiation of fatty streaks and atherosclerotic lesions in the vascular walls. 13,14 An increased risk of hyperlipidemia with the use of sirolimus has been observed in a number of investigations. Sirolimus increases total triglyceride as well as LDL levels in renal transplant recipients. The effect is dose dependent and is related to increased production of triglyceride-rich lipoproteins and/or decreased removal of these lipoproteins from the bloodstream. 15 Statins Decrease Hyperlipidemia, Cardiovascular Events, and Mortality Statins decrease total cholesterol, LDL-cholesterol, and triglyceride levels and often increase HDL-cholesterol levels. The impact of statins on hyperlipidemia and major coronary events has been demonstrated in many different primary or secondary prevention trials. Most of the trials have shown a significant reduction in cardiovascular events in patients receiving statin therapy, and in some studies, this reduction has been associated with decreased mortality. 16 The benefit from statin use has also been observed in the elderly population. 17,18 Although data on the use of statin therapy following renal transplantation are limited, uncontrolled studies support the use of statins in patients with endstage renal disease (ESRD), as well as in renal transplant recipients. In a retrospective analysis of data from a cohort of 3,716 ESRD patients initiating dialysis in 1996 and early 1997, Seliger et al 19 suggested that the use of statins is associated with a 32% decrease in all-cause mortality and a 37% decrease in cardiovascular-related mortality. An analysis by Cosio et al 20 demonstrated that when controlled for recipient age, serum cholesterol level, and transplant year, patients who received a statin had a 24% reduction in mortality compared with those who were not treated with statins. The ALERT Trial The Assessment of LEscol in Renal Transplantation (ALERT) trial is the first large-scale study to explore the potential benefits of statin therapy in renal allograft recipients. This investigator-initiated and investigator-led, multicenter, randomized, double-blind, placebo-controlled study assessed the effects of fluvastatin on cardiac and renal endpoints. Results were presented at the American Transplant Congress and at the World Congress of Nephrology 2003 meetings and reported by Dr. Hallvard Holdaas and colleagues in the June 14, 2003, issue of The Lancet. 22 Significant findings are reviewed below. The primary endpoint of the study was to compare the long-term effect of treatment with fluvastatin vs placebo on survival without the occurrence of a major adverse cardiac event (MACE). MACE was defined as cardiac death, nonfatal myocardial infarction (MI), or coronary intervention (coronary-artery bypass graft [CABG] surgery or percutaneous coronary intervention [PCI]). The secondary endpoints were composite cardiac, cardiovascular, and renal endpoints, as well as effects on the lipid profile, and safety and tolerability. Characteristics of Study Population Conducted at nephrology and transplant centers in nine different countries, the study enrolled a total of 2,102 patients who had renal or combined renal and pancreatic 4

7 Fluvastatin in Renal Transplant Recipients transplants 6 or more months before and followed them for a minimum of 5 years and a maximum of 6 years. All patients were between 30 and 75 years of age and were enrolled from June 1996 to October Patients were randomized to receive either fluvastatin (n = 1,050) or placebo (n = 1,052). The dosage of fluvastatin used was 40 mg/d for the first 2 years of the study; this was later increased to 80 mg/d based on recommendations of the safety monitoring board and data emerging from clinical outcomes trials. In the fluvastatin treatment group, 888 of the 1,050 patients (84.6%) completed follow-up, and 665 of those patients remained on the assigned study medication. In the placebo treatment group, 900 of the 1,052 patients (85.6%) completed follow-up, and 644 patients remained on the assigned study medication. All of the patients were clinically stable at the time of enrollment and had a total cholesterol level between 4 and 9 mmol/l ( mg/dl). Ineligible were transplant recipients who had suffered an MI within the past 6 months, who were already on a statin, who had a family history of hypercholesterolemia, who had experienced an acute transplant rejection in the previous 3 months, or who had a life expectancy of less than 1 year. Table 2 lists the baseline characteristics of the patients enrolled in the study. The age and the sex distribution in the fluvastatin and placebo treatment groups were similar. There was no significant difference in the baseline blood pressure and cholesterol values between the two groups, and there were equal numbers of diabetics in both groups. The principal cause of renal failure in both groups was glomerulonephritis. Most of the patients were first-time renal transplant recipients and had received a kidney from a diseased person. All patients were receiving cyclosporine. Usage of concomitant immunosuppressive medications was similar in both groups. The cardiovascular risk profiles were similar in the two groups, and 95% of the patients in both groups were taking some type of cardioprotective drug. The distribution of different classes of cardiovascular agents was similar in the two groups: 61.8% of the recipients in the fluvastatin treatment group were taking beta-adrenergic Table 2 ALERT Trial: Baseline Characteristics of Study Population Fluvastatin Placebo (n = 1,050) (n = 1,052) Demographics Mean age 49.5 yr 50.0 yr Males 66.8% 65.2% Mean diastolic blood pressure 85.6 mm Hg 85.6 mm Hg Mean systolic blood pressure mm Hg 144 mm Hg Mean body mass index (BMI) 25.8 kg/m² 25.8 kg/m² Mean total cholesterol level 248 mg/dl 251 mg/dl (6.4 mmol/l) (6.5 mmol/l) Mean LDL-cholesterol level 159 mg/dl 159 mg/dl (4.1 mmol/l) (4.1 mmol/l) Mean HDL-cholesterol level 50 mg/dl 54 mg/dl (1.3 mmol/l) (1.4 mmol/l) Mean triglyceride level 85 mg/dl 85 mg/dl (2.2 mmol/l) (2.2 mmol/l) Transplant details First transplantation 85.1% 85.6% Type of last transplant Live donor 22.9% 21.8% Diseased donor 77.0% 78.1% Mean (SD) serum creatinine 147 µmol/l 143 µmol/l level (54.4%) (51%) Immunosuppressive therapy concomitant with cyclosporine Azathioprine 65.1% 64.6% Prednisone 81.0% 80.6% Cyclophosphamide 0.9% 1.0% Mycophenolate mofetil 15.9% 15.1% Other 18.9% 21.3% Cardiovascular risk factors History of angina pectoris 6.8% 7.3% Previous myocardial infarction 3.0% 3.2% Diabetes 18.8% 18.9% Hypertension 76.0% 73.9% History of cerebrovascular disease 5.9% 5.7% History of peripheral vascular 7.6% 7.4% disease Current smoker 19.4% 17.6% Known family history of 8.7% 11.8% coronary heart disease Adapted from Holdaas et al 22 blockers, compared with 59.6% in the placebo treatment group, and 49.5% in the fluvastatin treatment group were receiving an angiotensin-converting enzyme (ACE) inhibitor or angiotensin II receptor antagonist, compared with 50.3% in the placebo treatment group. Sixty-five percent of patients in both groups received the higher dose of study medication (80 mg/d of fluvastatin or an equivalent placebo dose) after a mean follow-up of 2.8 years. About 14% of patients in the placebo treatment group and 7% in the fluvastatin treatment group took other lipid-lowering medications, mostly statins, during 5

8 Darshana Dadhania, MD Figure 1 Change in total cholesterol and LDL-cholesterol levels over time in patients receiving fluvastatin or placebo. Adapted from Holdaas et al. 21 Total cholesterol (mg/dl) Total cholesterol Fluvastatin Placebo LDL-cholesterol (mg/dl) LDL-cholesterol Fluvastatin Placebo Month the course of the study. Data were analyzed on an intentto-treat (ITT) basis. Significant Reductions in Total Cholesterol and LDL-cholesterol Figure 1 illustrates the change in the levels of total cholesterol and LDL-cholesterol in the fluvastatin and placebo treatment groups. There was a significant reduction in both parameters after 6 weeks of fluvastatin therapy, compared with baseline values. A further reduction was noted with an increase in fluvastatin dosage from 40 to 80 mg/d after a mean of 2.8 years of therapy. Overall results of the ALERT trial compared favorably with other major statin trials in reducing LDL-cholesterol levels and the rate of coronary heart disease (Table 3). During the course of this study, 66.3% of the patients in the fluvastatin treatment group achieved levels of total cholesterol recommended for prevention of coronary heart disease, and 74.2% achieved the recommended levels of LDL-cholesterol. During the latter part of the study, the mean total cholesterol level achieved was less than 200 mg/dl, and the LDL-cholesterol level was less than 108 mg/dl, meeting the requirements of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. 23 Significant Reduction in Cardiac Deaths and Nonfatal Myocardial Infarction Table 4 shows the number of individuals who reached the study endpoints in the fluvastatin and placebo treatment groups on an ITT basis. There was a 17% reduction in the primary endpoint (MACE) in the fluvastatin treatment group, compared with that in the group receiving placebo (P = 0.139). This is the first published study that Table 3 LDL-Cholesterol Levels and Coronary Heart Disease Rates in Major Statin Trials Baseline Net change in Percent Annual rate Percent Percent Sample LDL-C [mg/dl LDL-C [mg/dl change in of CHD reduction reduction in Trial* size (n) (mmol/l)] (mmol/l)] LDL-C (events/yr) in CHD cardiac deaths AFCAPS/TexCAPS 6, (3.9) 39 (1.0) 25% % NA ALERT 2, (4.1) 39 (1.0) 32% % 38% ALLHAT 10, (3.8) 23 (0.6) 30% 1.7 9% 0% ASCOT-LLA 10, (3.4) 39 (1.0) 29% % NA CARE 4, (3.6) 39 (1.0) 28% % 20% HPS 20, (3.4) 39 (1.0) 30% % 18% LIPID 9, (3.9) 35 (0.9) 25% % 24% LIPS 1, (3.4) 35 (0.9) 27% % 47% PROSPER 5, (3.8) 39 (1.0) 27% % 24% 4S 4, (4.9) 66 (1.7) 35% % 42% WOSCOPS 6, (5.0) 50 (1.3) 26% % 33% CHD = coronary heart disease (cardiac deaths + myocardial infarction); LDL-C = low-density lipoprotein-cholesterol; NA = data not available * AFCAPS/TexCAPS = Air Force/Texas Coronary Atherosclerosis Prevention Study; ALERT = Assessment of LEscol in Renal Transplantation; ALLHAT = Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial; ASCOT-LLA = Anglo-Scandinavian Cardiac Outcomes Trial Lipid Lowering Arm; CARE = Cholesterol and Recurrent Events Trial; HPS = Heart Protection Study; LIPID = Long-term Intervention with Pravastatin in Ischæmic Disease; LIPS = Lescol Interven tion Prevention Study; PROSPER = PROspective Study of Prava statin in the Elderly at Risk; 4S = Scandinavian Simvastatin Survival Study; WOSCOPS = West of Scotland Coronary Prevention Study Placebo-subtracted change from baseline Compared with baseline values Including unstable angina Including silent myocardial infarction and resuscitated cardiac arrest 6

9 Fluvastatin in Renal Transplant Recipients Table 4 ALERT Trial: Effects of Fluvastatin on Primary and Secondary Endpoints Fluvastatin Placebo (n = 1,050) (n = 1,052) P value Risk ratio (95% CI) Primary endpoint MACE (cardiac death or definite or probable ( ) nonfatal MI or CABG/PCI) Secondary endpoints Cardiac death ( ) Definite nonfatal MI ( ) Cardiac death or definite nonfatal MI ( ) Cardiac death or definite or probable nonfatal MI ( ) CABG ( ) PCI ( ) Fatal or nonfatal cerebrovascular event ( ) Noncardiovascular deaths ( ) All-cause deaths ( ) Graft loss or doubling of serum creatinine level ( ) CABG = coronary artery bypass grafting; MI = myocardial infarction; PCI = percutaneous coronary intervention Adapted from Holdaas et al 22 shows the effect of any statin on the occurrence or time to occurrence of MACE in renal transplant patients. Of the secondary endpoints, there was a significant reduction in cardiac deaths and definite nonfatal MI in the fluvastatin treatment arm (Table 4). The combined endpoint of cardiac death or definite nonfatal MI was associated with a 35% risk reduction (P = 0.005). Interpreting Results for Other Endpoints The overall rate for cardiac events in the ALERT trial was lower than expected, and the trial may not have been sufficiently powered to detect a significant reduction in the primary endpoint of MACE. The limitations in analyzing the primary endpoint suggest that secondary endpoints may also need to be interpreted cautiously. Although there were no significant reductions in noncardiovascular deaths and renal composite endpoints in the group receiving fluvastatin, it should be noted that total cholesterol and LDL-cholesterol levels were not associated with these endpoints in the group that did not receive lipid-lowering statin therapy. The rates of cardiac intervention (CABG or PCI) also Table 5 Clinically Relevant Statin Drug Interactions did not differ significantly between the two groups. The ALERT trial was not originally designed to detect an effect on all-cause mortality, and the absence of such an effect was not unexpected, according to Dr. Holdaas, considering the size of the trial. Safety Profile Expanded Many statins are metabolized in the liver by enzymes in the CYP3A4 pathway and present a huge potential for drug-drug interaction. Unlike most other statins, fluva statin is not metabolized by the CYP3A4 pathway but by the CYP2C9 pathway, which displays very limited drug-drug interactions. Fluvastatin has far fewer clinically relevant drug interactions compared with other statins (Table 5). 24 Drug/drug class Atorvastatin Fluvastatin Lovastatin Pravastatin Rosuvastatin Simvastatin Azole antifungals Calcium-channel + + blockers Cyclosporine Erythromycin Gemfibrozil HIV protease + + NA + inhibitors Niacin + + NA + Warfarin = Drug interaction reported; = no reaction reported; NA = data not available. Adapted from Jacobson 24 7

10 Darshana Dadhania, MD The known safety database of fluvastatin was borne out in the ALERT trial and expanded for the renal transplant population. The number of adverse events was similar in both groups. Approximately 15% of patients in the fluvastatin treatment group and 16% in the placebo treatment group experienced some clinical or laboratory abnormality that required discontinuation of the study drug. Unlike other statins, fluvastatin is not associated with high rates of elevation of serum creatinine kinase. In the ALERT trial, the number of patients with abnormal levels of serum creatinine kinase or alanine transaminase did not differ significantly between the fluvastatin and placebo treatment groups. Conclusion and Implications The ALERT trial is the first large-scale, controlled study evaluating the effects of a statin in renal transplant recipients and the first study to demonstrate an effect of any statin on the occurrence or time to occurrence of MACE in this population. Given the high rate of cardiovascular deaths in the renal transplant cohort, this was an important study. Data from the trial demonstrate that fluvastatin is safe and efficacious in lowering the levels of total cholesterol, LDL-cholesterol, and triglycerides. It is noteworthy that renal transplant patients treated with fluvastatin reached the recommended levels for coronary heart disease prevention and that target cholesterol levels were accomplished without an increase in adverse events. Unlike other statins, fluvastatin was not associated with increased adverse side effects in renal transplant recipients taking the immunosuppressive drug cyclosporine. A similar number of patients in both the fluvastatin and placebo treatment groups reached the composite renal endpoint of graft loss or doubling of the serum creat i nine level. Whether a more detailed evaluation that includes renal histology and measurement of the glomerular filtration rate would unmask benefits of statin therapy is an issue that remains unexplored. Also unresolved is whether therapy with statins would be of value in patients with chronic allograft nephropathy. References 1. Ojo AO, Hanson JA, Wolfe RA, Leichtman AB, Agodoa LY, Port FK. Long term survival in renal transplant recipients with graft function. Kidney Int. 2000;57: van Dijk PC, Jager KJ, de Charro F, et al. Renal replacement therapy in Europe: the results of a collaborative effort by the ERA- EDTA registry and six national or regional registries. Nephrol Dial Transplant. 2001;16: Arend SM, Mallat MJ, Westendorp RJ, van der Woude FJ, van Es LA. Patient survival after renal transplantation: more than 25 years follow-up. Nephrol Dial Transplant. 1997;12: Dimeny EM. Cardiovascular disease after renal transplantation. Kidney Int. 2002;61(suppl 80):S78 S Kasiske BL, Chakkera HA, Roel J. Explained and unexplained ischemic heart disease risk after renal transplantation. J Am Soc Nephrol. 2000;11: Kasiske BL. Hyperlipidemia in patients with chronic renal disease. Am J Kidney Dis. 1998;32(suppl 3):S142 S Aakhus S, Dahl K, Wideroe TE. Hyperlipidæmia in renal transplant patients. J Intern Med. 1996;239: Andany MA, Kasiske BL. Dyslipidemia and its management after renal transplantation. J Nephrol. 2001;14(suppl 4):S81 S Ballantyne CM, Podet EJ, Petsch WP, et al. Effects of cyclosporin therapy on plasma lipoprotein levels. JAMA. 1989;262: Taskinen MR, Kuusi T, Yki-Järvinen H, Nikkila KA. Shortterm effects of prednisone on serum lipids and high density lipoprotein subfractions in normolipidemic healthy men. J Clin Endocrinol Metab. 1986;67: Ettinger WH, Hazzard WR. Prednisone increases very low density lipoprotein and high density lipoprotein in healthy men. Metabolism. 1988;37: Hricik DE, Mayes JT, Schulak JA. Independent effects of cyclosporine and prednisone on posttransplant hypercholesterolemia. Am J Kidney Dis. 1991;18: Varghese Z, Fernando RL, Turakhia G, et al. Calcineurin inhibitors enhance low-density lipoprotein oxidation in transplant patients. Kidney Int. 1999;56(suppl 71):S137 S Ghanem H, van den Dorpel MA, Weimar W, Man in T Veld AJ, El-Kannishy MH, Jansen H. Increased low density lipoprotein oxidation in stable kidney transplant recipients. Kidney Int. 1996;49: Morrisett JD, Abdel-Fattah G, Hoogeveen R, et al. Effects of sirolimus on plasma lipids, lipoprotein levels, and fatty acid metabolism in renal transplant patients. J Lipid Res. 2002;43: Lousberg TR, Denham AM, Rasmussen JR. A comparison of clinical outcome studies among cholesterol-lowering agents. Ann Pharmacother. 2001;35: Shepherd J, Blauw GJ, Murphy MB, et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomized controlled trial. Lancet. 2002;360: Maycock CAA, Muhlestein JB, Horne BD, et al. Statin therapy is associated with reduced mortality across all age groups of individuals with significant coronary disease, including very elderly patients. J Am Coll Cardiol. 2002;40: Seliger SL, Weiss NS, Gillen DL, et al. HMG-CoA reductase inhibitors are associated with reduced mortality in ESRD patients. Kidney Int. 2002;61: Cosio FG, Pesavento TE, Pelletier RP, et al. Patient survival after renal transplantation, III: the effects of statins. Am J Kidney Dis. 2002;40: Holdaas H, Fellström B, Jardine A, et al. Randomized double blind trial of fluvastatin for hypercholesterolemia in renal transplant recipients. ALERT Study Group. Paper presented at: American Transplant Congress 2003; May 30 June 4, 2003; Washington, DC. Abstract Holdaas H, Fellström B, Jardine AG, et al. Effect of fluvastatin on cardiac outcomes in renal transplant recipients: a multicenter, randomized, placebo-controlled trial. Lancet. 2003;361: Executive summary of the third report of the National Cholesterol Education Program (NECP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III). JAMA. 2001;285: Jacobson TA. Combination lipid-lowering therapy with statins: safety issues in the postcerivastatin era. Expert Opin Drug Saf. 2003;2:

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