Correspondence
Drugs in Cardiac Transplantation
N Engl J Med 1996; 334:400-402February 8, 1996
- Article
To the Editor:
Kobashigawa and coworkers (Sept. 7 issue)1 report that therapy with pravastatin beginning shortly after transplantation led to a reduction in the rates of hemodynamically important cardiac rejection and mortality and a lower incidence of coronary vasculopathy. Patients treated with pravastatin had total cholesterol and low-density lipoprotein (LDL) cholesterol levels that were 22 percent and 27 percent, respectively, lower than those in the control patients during the first year after transplantation. Natural-killer-cell cytotoxicity was also lower in the pravastatin group, and the authors speculate about the potential mechanisms whereby pravastatin may cause an increased state of immunosuppression. The authors do not consider a straightforward mechanism whereby marked reductions in serum lipoproteins may influence cyclosporine activity. Cyclosporine is highly bound to blood components, with approximately 50 percent of whole-blood cyclosporine bound to erythrocytes and 15 percent bound to leukocytes. The rest is present in plasma, and the majority is exclusively bound to lipoproteins. As suggested in the article by Keogh et al.2 in the same issue of the Journal, “a decrease in the level of low-density lipoprotein (LDL) reduces the level of LDL-bound cyclosporine, leaving a higher level of free cyclosporine.” This could lead to differences in the biologic activity of cyclosporine, even in the presence of similar whole-blood trough levels.
Keogh et al. also report that ketoconazole reduces the need for cyclosporine after cardiac transplantation.2 The accompanying editorial by Valantine and Schroeder3 raises the question of how one should use the results of small, single-center studies and concludes that most physicians “will apply the results of these two studies to management decisions that will undoubtedly benefit their patients.” Before physicians begin to treat all patients with ketoconazole and pravastatin immediately after transplantation, they should consider the letter by Lees and Lees4 in the same issue of the Journal, which describes a case of rhabdomyolysis resulting from the concomitant administration of lovastatin and the antifungal agent itraconazole. The azole-derivative antifungal agents inhibit cholesterol biosynthesis at a point different from that of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors. They have previously been reported to cause rhabdomyolysis in patients receiving immunosuppressive therapy with cyclosporine and lipid-lowering therapy with lovastatin and simvastatin. Although data are not available on the safety of azole derivatives in combination with cyclosporine and pravastatin, this combination should be used with caution. Pharmacokinetic studies in rats treated with pravastatin, lovastatin, and simvastatin showed that for all three agents, coadministration of cyclosporine results in increased systemic exposure and a high incidence of rhabdomyolysis.5
5 ReferencesChristie M. Ballantyne, M.D.
Baylor College of Medicine, Houston, TX 770301
Kobashigawa JA ,Katznelson S ,Laks H , et al. Effect of pravastatin on outcomes after cardiac transplantation. N Engl J Med 1995;333:621-627
Full Text | Web of Science | Medline2
Keogh A ,Spratt P ,McCosker C ,Macdonald P ,Mundy J ,kaan A . Ketoconazole to reduce the need for cyclosporine after cardiac transplantation. N Engl J Med 1995;333:628-633
Full Text | Web of Science | Medline3
Valantine HA ,Schroeder JS . Recent advances in cardiac transplantation. N Engl J Med 1995;333:660-661
Full Text | Web of Science | Medline4
Lees RS ,Lees AM . Rhabdomyolysis from the coadministration of lovastatin and the antifungal agent itraconazole. N Engl J Med 1995;333:664-665
Full Text | Web of Science | Medline5
Smith PF ,Eydelloth RS ,Grossman SJ , et al. HMG-CoA reductase inhibitor-induced myopathy in the rat: cyclosporine A interaction and mechanism studies. J Pharmacol Exp Ther 1991;257:1225-1235
Web of Science | Medline
To the Editor:
The article by Keogh et al. on manipulating the metabolic interaction between ketoconazole and cyclosporine in cardiac-transplant recipients is imprecise in stating that “the mechanism of the interaction is not clear.” Considerable data document the role of the specific cytochrome P-450 3A3/4 in the metabolism of cyclosporine, in both the liver and the small intestine.1,2 Ketoconazole is well known as a potent, specific inhibitor of cytochrome P-450 3A3/4 at levels found in vivo.3 Maintenance therapy with such a specific, potent inhibitor also creates the opportunity for further interaction with other drugs metabolized by cytochrome P-450 3A3/4. This problem can be rationally approached if the nature of the interaction is understood and drugs (such as terfenadine) that are cytochrome P-450 3A3/4 substrates with known or expected toxicity after metabolic interference are avoided or used with caution.
3 ReferencesLisa L. von Moltke, M.D.
David J. Greenblatt, M.D.
Tufts University School of Medicine, Boston, MA 021111
Kronbach T ,Fischer V ,Meyer UA . Cyclosporine metabolism in human liver: identification of a cytochrome P-450III gene family as the major cyclosporine-metabolizing enzyme explains interactions of cyclosporine with other drugs. Clin Pharmacol Ther 1988;43:630-635
CrossRef | Web of Science | Medline2
Watkins PB . Drug metabolism by cytochromes P450 in the liver and small bowel. Gastroenterol Clin North Am 1992;21:511-526
Web of Science | Medline3
Gomez DY ,Wacher VJ ,Tomlanovich SJ ,Hebert MF ,Benet LZ . The effects of ketoconazole on the intestinal metabolism and bioavailability of cyclosporine. Clin Pharmacol Ther 1995;58:15-19
CrossRef | Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: The exact mechanism whereby pravastatin may cause an increased state of immunosuppression remains unclear. I agree with Dr. Ballantyne that potentiation of free cyclosporine due to marked reductions in serum lipoproteins may play some part in this mechanism. However, in our study, 5 of 14 episodes of cardiac rejection accompanied by hemodynamic compromise occurred between one and two months after cardiac transplantation. During this time, trough cyclosporine blood levels were similar in both groups, whereas cholesterol levels were not yet significantly different between the pravastatin and control groups. To investigate interactions between cyclosporine and pravastatin further, we are currently conducting pharmacokinetic studies of the two drugs in cardiac-transplant recipients. The findings of significant decreases in natural-killer-cell cytotoxicity and in the rate of rejection accompanied by hemodynamic compromise in the pravastatin group (including the period soon after transplantation) suggest a possible direct immunosuppressive effect of the HMG-CoA reductase inhibitor. In addition, a recent large, randomized trial of pravastatin in patients treated for asymptomatic hyperlipidemia who had not undergone transplantation demonstrated a reduction in cardiovascular events in the pravastatin-treated group beginning six months after the start of the study.1 One might speculate that similar cardiovascular protective effects may also be occurring in our transplant recipients who were treated with pravastatin.
The combination of cyclosporine, pravastatin, and ketoconazole should be used with caution because of concern about the development of myositis, rhabdomyolysis, or both. In our experience and that of Yoshimura et al.,2 pravastatin appears to have a low incidence of causing myositis, rhabdomyolysis, or both in transplant recipients. In our study, myositis or rhabdomyolysis did not develop with the concomitant use of pravastatin and cyclosporine; however, we did not routinely give ketoconazole to our patients. In a study in rats of the viability of striated muscle,3 the lipophilic HMG-CoA reductase inhibitors lovastatin and simvastatin decreased the number of viable cells by 50 percent at concentrations of 5.0 μmol and 1.3 μmol; in contrast, a concentration of 300 μmol of the hydrophilic drug pravastatin was needed to produce the same effect. Hence, the descending order of potency of an adverse effect on the viability of rat myoblast cells was as follows: simvastatin, lovastatin, and pravastatin. This order may be an important factor in the observed low incidence of myositis and rhabdomyolysis in cardiac-transplant recipients treated with pravastatin.
As a result of our study, we are now using pravastatin as routine therapy immediately after cardiac transplantation, regardless of the patient's cholesterol levels.
3 ReferencesJon Kobashigawa, M.D.
UCLA School of Medicine, Los Angeles, CA 90095-14051
Shepherd J ,Cobbe SM ,Ford I , et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med 1995;333:1301-1307
Full Text | Web of Science | Medline2
Yoshimura N ,Oka T ,Okamoto M ,Ohmori Y . The effects of pravastatin on hyperlipidemia in renal transplant recipients. Transplantation 1992;53:94-99
CrossRef | Web of Science | Medline3
Gadbut AP ,Caruso AP ,Galper JB . Differential sensitivity of C2-C12 striated muscle cells to lovastatin and pravastatin. J Mol Cell Cardiol 1995;27:2397-2402
CrossRef | Web of Science | Medline
Author/Editor Response
The hypothesis that pravastatin reduces cyclosporine bound to LDL cholesterol, leaving a higher proportion of free cyclosporine, is being explored. We have unpublished data showing that lipid-lowering agents do indeed increase the proportion of free cyclosporine and that free cyclosporine levels correlate with the severity of rejection.
Contrary to Dr. Ballantyne's interpretation, we advocate ketoconazole as a safe option, particularly for patients or health systems under financial duress. We have data on the combined use of azole derivatives and “statin” drugs in cardiac-transplant recipients. Ketoconazole has been used with pravastatin or simvastatin (each at a dose of 10 to 20 mg per day) in 50 patients for up to four years without a case of rhabdomyolysis, and diltiazem (another inhibitor of cytochrome P-450) has been used with pravastatin or simvastatin in 60 patients with similar results. In one recipient of a single-lung transplant, rhabdomyolysis developed during therapy with 20 mg of simvastatin per day and 200 mg of itraconazole twice daily. Surveillance of creatine kinase levels and early reporting of myalgia remain important. After transplantation, hydrophilic pravastatin appears the least likely and lovastatin the most likely to cause rhabdomyolysis, and simvastatin lies in between the two. Equivalent doses of statins are not equivalent in their cholesterol-lowering effects, and this may partly explain the difference.1
Are statins worth the risk? Vasculopathy causes 14 percent of deaths after transplantation.2 Our incidence of rhabdomyolysis with pravastatin or simvastatin is less than 1 in 150. The benefits of pravastatin in reducing coronary disease in transplants, hemodynamic rejection, and mortality will certainly outweigh this risk.
It is possible that ketoconazole not only may inhibit hepatic metabolism of cyclosporine but, like diltiazem (another inhibitor of cytochrome P-450), also may improve its own bioavailability through the inhibition of cytochrome P-450 in the gut wall, leading to increases in peak cyclosporine levels and in the area under the curve.3-5 We agree that transplantation units that use ketoconazole must understand the potential for interactions. This is analogous to the use of cyclosporine, whose complex interactions must be understood in order to administer it safely.
5 ReferencesAnne M. Keogh, M.B., B.S., M.D.
Phillip Spratt, M.B., B.S.
St. Vincent's Hospital, Darlinghurst 2010, NSW, Australia1
Lintott CJ ,Scott RS ,Sutherland WH ,Bremer J . Treating hypercholesterolaemia with HMG CoA reductase inhibitors: a direct comparison of simvastatin and pravastatin. Aust N Z J Med 1993;23:381-386
CrossRef | Medline2
Keogh AM ,Kaan A . The Australian and New Zealand Cardiothoracic Organ Transplant Registry: first report 1984-1992. Aust N Z J Med 1992;22:712-717
CrossRef | Medline3
Valantine H ,Keogh A ,McIntosh N ,Hunt S ,Oyer P ,Schroeder J . Cost containment: coadministration of diltiazem with cyclosporine after heart transplantation. J Heart Lung Transplant 1992;11:1-8
Web of Science | Medline4
Macdonald P ,Keogh A ,Connell J ,Harvison A ,Richens D ,Spratt P . Diltiazem co-administration reduces cyclosporine toxicity after heart transplantation: a prospective randomised study. Transplant Proc 1992;24:2259-2262
Web of Science | Medline5
Potter J, Taylor P, Rigby R. Diltiazem as a cyclosporine sparing agent in renal transplant recipients. Transplant Proc (in press). abstract.
Author/Editor Response
Ballantyne emphasizes the need for caution when one is using HMG-CoA reductase inhibitors, azole-derivative antifungal agents, or both in combination with cyclosporine. She cites a report of a higher incidence of rhabdomyolysis in rats when this combination was used. In fact, this problem has already been addressed extensively in patients treated with lovastatin,1,2 pravastatin,3 and simvastatin.4 These careful analyses indicate that the serum concentration of the HMG-CoA reductase inhibitor is increased severalfold when the drug is used in combination with cyclosporine, because of metabolic competition.
It is clear that the dose of the HMG-CoA reductase inhibitor must be decreased considerably in patients treated with cyclosporine, with a maximal target dose of 20 mg per day. This approach has been used quite successfully, and the use of these agents should not be considered an absolute contraindication, given the potential benefit that may result. This is particularly true with respect to decreasing the risk of atherosclerosis in transplants and for coronary-artery events associated with this complication. It is clear that the initial experience of rhabdomyolysis in heart-transplant recipients treated with HMG-CoA reductase inhibitors affected physicians' practice, such that many patients have not been treated for their severe dyslipidemia. This is unfortunate because, given the vascular injury to the heart at the time of transplantation and as a consequence of rejection, these patients, perhaps even more than patients who do not undergo transplantation, require vigorous control of dyslipidemia.
4 ReferencesHannah A. Valantine, M.D.
Stanford University School of Medicine, Stanford, CA 94305-52461
Velosa JA ,La Belle P ,Ronca PD , et al. Pharmacokinetics of lovastatin in renal transplant patients on azathioprine or cyclosporine. J Am Soc Nephrol 1990;1:325-325 abstract.2
Kobashigawa JA ,Murphy FL ,Stevenson LW , et al. Low-dose lovastatin safely lowers cholesterol after cardiac transplantation. Circulation 1990;82:Suppl 4:IV-2813
Regazzi MB ,Iacona I ,Campana C , et al. Altered disposition of pravastatin following concomitant drug therapy with cyclosporin A in transplant recipients. Transplant Proc 1993;25:2732-2734
Web of Science | Medline4
Arnadottir M ,Eriksson LO ,Thysell H ,Karkas JD . Plasma concentration profiles of simvastatin 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitory activity in kidney transplant recipients with and without ciclosporin. Nephron 1993;65:410-413
CrossRef | Medline
