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Treatment of hyperlipidemia after heart transplantation and rationale for the heart transplant lipid registry
Treatment of Hyperlipidemia After Heart Transplantation and Rationale for the Heart Transplant Lipid Registry Christie M. Ballantyne, MD, Robert C. Bourge, MD, Leslie J. Domalik, MD, Howie J. Eisen, MD, Daniel P. Fishbein, MD, Spencer H. Kubo, MD, Kathleen D. Lake, PharmD, Branislav Radovancevic, MD, David 0. Taylor, MD, Hector 0. Ventura, MD, Clyde W. Yancy, Jr., MD, and James B. Young, MD Hyperlipidemia occurs frequently after heart transplantation, and accelerated coronary artery disease remains the major cause of morbidity and mortality in patients who survive more than 1 year after heart transplantation. However, the risks and benefits of lipid-lowering therapy after heart transplantation remain poorly defined, and national guidelines for lipid-lowering drug therapy do not specifically address treatment of dyslipidemia in transplant recipients. Since the initial reports in the 1980s of rhabdomyolysis in heart transplant patients receiving high-dosage lovastatin, results of 11 post-transplantation series that used lovastatin, simvastatin, or pravastatin at lower dosages as drug monotherapy have been published. These studies have shown an overall 1% incidence of rhabdomyolysis, defined as creatine kinase > 10 times the upper limit of
normal plus muscle symptoms. One randomized, controlled prospective trial has investigated the effects of lipid-lowering pharmacotherapy on patient outcome in cardiac transplant recipients. At 1-year follow-up in this nonblinded, single-center trial, patients treated with pravastatin (20 or 40 mg/day) initiated within 2 weeks of transplantation had a significant reduction in mortality rate and a significantly lower incidence of transplant arteriopathy. A number of important issues remain unanswered regarding treatment guidelines in patients with hyperlipidemia after heart transplantation. In January 1995 we began the Heart Transplant lipid Registry, with 12 participant centers, to gather data prospectively on the efficacy and safety of lipid-lowering drugs in the treatment of dyslipidemia after heart transplantation. (Am J Cardiol 1996;78:532-535)
ore than 30,000 cardiac transplants have been M reported to the Registry of the International Society for Heart and Lung Transplantation since
solved questions concerning practical therapeutic issues, and presents the rationale for the recently instituted Heart Transplant Lipid Registry.
1983; almost 3,000 were performed in 1994.’ With increasing numbers of heart transplants and improved l-year survival rates, more patients face the problem of accelerated atherosclerotic coronary artery disease (CAD), the leading cause of morbidity and mortality among those surviving > 1 year.* Treatment of hyperlipidemia in patients with CAD has been shown to slow lesion progression and to reduce CAD morbidity along with both CAD and all-cause mortality rates.3*4 The adult treatment guidelines of the National Cholesterol Education Program’ emphasize CAD risk status as a guide to the intensity of lipid-lowering therapy. Individuals with the greatest probability of having a CAD event within the next 5 to 10 years are candidates for the most aggressive intervention. The guidelines, however, do not specifically address management of hyperlipidemia in heart transplant recipients. This article reviews the available data on treatment of hyperlipidemia in these patients, discusses unreFrom the Section of Atherosclerosis, Department of Medicine, Baylor College of Medicine, Houston, Texas, on behalf of the Heart Transplant Lipid Registry. This work was supported by a grant from Merck and Co., Inc, West Point, Pennsylvania. Manuscript received December 15, 1995; revised manuscript received and accepted March 22, 1996. Address for reprints: Christie M. Ballantyne, MD, Department of Medicine, MS A-601, Baylor College of Medicine, 6565 Fannin Street, Houston, Texas 77030.
532
0 1996 by Excerpta Medica, All riahts reserved.
Inc.
SCOPE OF THE PROBLEM Many studies have clearly documented that hyperlipidemia is common after heart transplantation.6*7 In 1 series, low-density lipoprotein (LDL) cholesterol remained 2130 mg/dl in 64% of patients; plasma triglyceride remained 2200 mg/dl in 41% of patients 6 months after postoperative dietary instruction*; and more than 85% of patients had LDL cholesterol 2 100 mg/dl despite dietary therapy. The high frequency of hyperlipidemia is clearly multifactorial and related to immunosuppressive therapy, weight gain, and previous history of hyperlipidemia. Cyclosporine has been shown to increase LDL cholesterol concentrations significantly. The frequency of transplant arteriopathy varies widely among studies, which may reflect either differences in methods of detection or true variations in incidence among centers due to differences in medical management. Multiple studies-most commonly, retrospective analyses of data from single institutions-have examined risk factors for transplant arteriopathy. The studies have varied in the risk factors evaluated, follow-up period, and definition of CAD, and results have been conflicting. Nevertheless, the cumulative data suggest that the development of transplant CAD is influenced by both immune and nonimmune factors. Although a relation 0002-9149/96/Q 15.00 PII 50002-9149(96)00358-X
with hyperlipidemia has been demonstrated by multiple studies, some have shown a correlation with elevations of total or LDL cholesterol,9~10others with plasma triglyceride, ’ l-l3 and yet others have found no correlation with either cholesterol or triglyceride.* In animal models, however, hyperlipidernia consistently accelerates the development of allograft arteriopathy. It is highly probable that hyperlipidemia plays a role in the development of CAD after transplantation, but it is difficult to estimate its relative contribution to the risk.
BENEFITS AND RISKS OF UPIDLOWERING DRUG THERAPY AFTER HEART TRANSPLANTATION Guidelines for lipid-lowering drug therapy have been formulated to optimize its benefits while minimizing its risks. Long-term randomized clinical trials have shown clear benefit from drug therapy in both patients with and without symptomatic CAD.14 The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) and nicotinic acid have been key agents in multiple secondary prevention trials, and benefit in healthy patients has been achieved with a resin, a fibrate, or a statin. In contrast to this wealth of data, only 1 randomized, controlled prospective trial has investigated the effects of lipid-lowering pharmacotherapy on outcome in cardiac transplant recipients. At l-year follow-up in this nonblinded, single-center trial, patients treated with pravastatin (20 or 40 mg/day, initiated within 2 weeks of transplantation; n=47) had a significant reduction in mortality rate, as well as a significantly lower incidence of transplant arteriopathy, as assessed by angiography and at autopsy, and significantly less lesion progression, as determined by intracoronary ultrasound.‘5 The pravastatin group also had significant reductions in hemodynamically significant rejection and natural killer cell cytotoxicity. There are several potential mechanisms whereby pravastatin may have caused an increased state of immunosuppression in this study. Statins have been shown to decrease antibodydependent cellular cytotoxicity and natural killer cell function.16 In addition, marked reductions in plasma lipoprotein concentrations might influence cyclosporine activity. The majority of cyclosporine in plasma is bound, exclusively, to lipoproteins. A marked decrease in lipoprotein concentrations would lead to an increased proportion of free cyclosporine in plasma. The result could be significant increases in the biologic activity of cyclosporine, even with similar whole blood trough levels.” Statins may have direct vascular effects on intimal proliferation. Simvastatin has been shown to reduce allograft arteriopathy without significant changes in lipoprotein concentrations in a rat model of heart transplantation with FK506 immunosuppressive therapy.” Inhibition of mevalonate products, such as famesyl-PP and geranyl-PP, by statins could inhibit cellular proliferation. l9
The low incidence of adverse side effects with lipid-lowering drug therapy in patients with native CAD has been clearly established in large, multicenter prospective trials, which have included many thousands of patient-years of follow-up.3,4 Risk for toxicity from lipid-lowering drugs is increased in transplant patients receiving cyclosporine and prednisone. The initial, enthusiastic report6 of post-transplantation lipid lowering using lovastatin at a high dosage (80 mg/day) was followed by reports of rhabdomyolysis.8S20It was found that 3-hydroxy-3methylglutaryl coenzyme A reductase inhibitory activity in plasma is markedly increased in patients given lovastatin in conjunction with cyclosporine and prednisone.8%21 The hypothesis that elevation of plasma concentrations of lovastatin and its (active) metabolites, owing to an interaction with immunosuppressive drugs, might be a mechanism for myopathy was further supported by a large prospective trial** that examined the safety of lovastatin therapy in hypercholesterolemic patients not receiving immunosuppressive therapy. The incidence of rhabdomyolysis-which was defined as creatine kinase elevation > 10 times the upper limit of normal with muscle symptoms-was dose dependent, varying from 0.02% ( l/4,933 patients) for dosages ~40 mg/ day to 0.24% (4/1,649 patients) at 80 mg/day.22 Administration of lovastatin concomitant with gemfibrozil, nicotinic acid, erythromycin, or itraconazole also increased the risk for rhabdomyolysis. Caution should be used in administering other drugs metabolized by the cytochrome P450 system (for example, macrolide antibodies, calcium channel blockers) to patients receiving both cyclosporine and a statin. Since the initial reports in the 1980s of rhabdomyolysis in heart transplant patients receiving high dosages of lovastatin, results of 11 post-transplantation series that used lovastatin, 8~21~23-*6 simvastatin, 27-30or pravastatin l5 as drug monotherapy have been published (Table I). These studies have shown a much lower incidence of rhabdomyolysis (defined as creatine kinase > 10 times the upper limit of normal with muscle symptoms) : lovastatin 1.l% (2/ 186)) simvastatin 1.4% ( l/7 1) , and pravastatin 0% (O/47), or 1.01% (3/304) overall. Unfortunately, the studies had limited follow-up periods and small numbers of patients, and all were from single centers. The four available statins-lovastatin, simvastatin, pravastatin, and (the most recently approved) fluvastatin-differ in pharmacokinetic profile with respect to hydrophilicity, first-pass extraction by the liver, plasma half-life, and protein binding. Pharmacokinetic studies have shown that cyclosporine interacts not only with lovastatin 21and simvastatin, 31 which are lipophilic, but also with pravastatin, which is more hydrophilic. In heart transplant recipients, coadministration of cyclosporine altered the disposition of pravastatin, including a 20-fold increase in the area under the curve and a I-/-fold increase in maximum plasma concentration (C,,,) .31 In rats treated with lovastatin, simvastatin, or pravastatin, coadministration of cyclosporine resulted in in-
PREVENTIVE CARDIOLOGY/HEART
TRANSPLANT LIPID REGISTRY 533
TABLE I Recent Clinical
Studies of SingleAgent Doily Dose
Study Kuo et al, 198923 Koboshigawa et al, 1 9902’ Ballantyne et al, 1992’ Peters et 01, 199324 Anguita et al, 1994= Hidalgo et al, 1 99526 Barbiretal,19912’ Vanhaecke et 01, 1 99428 Campano et al, 1 99429 Pflugfelder et al, 1 99530 Kobashigawa et al, 1 9951S
Statin Therapy
After Heart Transplantation
Follow-up ATG%
AHDL%
Myositis/ Myalgias
Rhabdomyolysis: lOxCK+ Symptoms
Drug
(msl
n
b-4
TC%
ALDL%
L L
20-60 10-20
11 44
15 (3-41) zz6
-27 -26
-34 -26
+5 -22
+5 -2
0 NR
L
20
15
13 (6-30)
-21
-31
-8
+8
1
0
1 1
20 lo-40
35 63
NR 13
-24 -15
NR -21
-5 -17
NR +3
0 2
L
10
18
2
-15
-21
-2
-2
1
0 1 (believed 2” to colchicine) 0
S S
10 5-15
12 26
8 12
-38 -27
-42 -40
-25 -21
+9 -2
0 0
0 1 (at 15 mg)
S
10
20
4
-12.5
-21.3
+lO
0
0
S
10
13
12
-24
-39
-21
+2
0
0
P
20-40
47
12
-22*
-27’
-32*
+21*
0
0
-4
0 1 (at 40 mg)
l Compared with control group (n = 50) rather than baseline value. CK = creatine kinare; HDL = highdensity lipoprotein cholesterol; 1 = lovastatin; LDL = lowdensity lipoprotein cholesterol; NR = not reported; P = pravastotin; S = simvastatin; TC = total cholesterol; TG = triglyceride; A = change.
creased systemic exposure, with a consequent increase in myopathy for each statin. No study using fluvastatin after heart transplantation has yet been published, although use for 14 weeks in 19 renal transplant recipients led to an asymptomatic increase in creatine kinase > 10 times the upper limit of normal in 1 patient.33 Although nicotinic acid has beneficial effects in mixed hyperlipidemia, which is frequently seen after heart transplantation, 65% of the heart transplant recipients in 1 study were unable to tolerate the agent because of adverse effects such as impaired glucose tolerance 34The bile acid-binding resins may interfere with’absorption of lipid-soluble drugs, such as cyclosporine, and also may raise plasma triglyceride concentrations. The fibrate gemfibrozil is well tolerated in heart transplant patients and leads to marked reductions in triglycerides.” However, reductions in total and LDL cholesterol concentrations are both more modest and variable, limiting treatment of severe hypercholesterolemia that often occurs after heart transplantation.*
1. What lipid values should be used as thresholds for initiation of drug therapy, and what should the lipid goals be? Should goals be based on LDL cholesterol alone or, on the basis of available clinical data, should plasma triglyceride also be considered? Should all patients receive lipid-lowering drug treatment regardless of lipid values? 2. When should drug therapy be initiated? In a recent study that showed benefits in transplant arteriopathy,” therapy was initiated 1 to 14 days after transplantation. Would waiting 6 to 12 weeks to assess lipid changes in patients on dietary therapy be less effective? 3. How much change in lipoprotein concentrations can be achieved by the available agents, and with how much toxicity? What factors predispose to the development of myopathy? 4. What is the relation between therapeutically induced changes in lipoprotein concentrations and clinical end points such as development of arteriopathy, rejection episodes, and all-cause mortality? 5. Are there clinically significant differences among the statins with regard to efficacy and safety? 6. What is the most cost-effective way to treat UNRESOLVED QUESTIONS If both immune and nonimmune risk factors are hyperlipidemia in heart transplant recipients? important in the development of transplant CAD, FOR THE HEART what reductions in morbidity and mortality from RATIONALE LIPID REGISTRY transplant CAD could theoretically be achieved with TRANSPLANT In January 1995, we began the Heart Transplant optimal lipid-lowering therapy? Although a clear answer to this question would require a large, multi- Lipid Registry, involving 12 centers, to gather procenter trial, the results of a single, prospective trial l5 spective data on the efficacy and safety of lipid-lowindicate that the benefit could be considerable. ering drugs in the treatment of dyslipidemia after Therefore, we would like to pose a number of im- heart transplantation. The registrjr is designed to corportant questions regarding drug treatment guide- relate information on the treatment of hundreds of lines in patients with hyperlipidemia after heart transplant recipients, with thousands of patient-years of follow-up, to provide a clearer picture of the litransplantation: 534
THE AMERICAN
JOURNAL
OF CARDIOLOGY@
VOL.
78
SEPTEMBER
1, 1996
poprotein changes achieved and the incidence of serious adverse effects. The data should be helpful for the design of larger, multicenter prospective trials, to address more definitively the question of the optimal treatment of dyslipidemia in heart transplant recipients for the reduction of morbidity and mortality from transplant arteriopathy. Furthermore, the data may also be useful in assessment of the most cost-effective way to treat dyslipidemia in this patient population. Acknowledgments: We thank Alistair Fyfe, MD, PhD, Evan Stein, MD, PhD, and Beth Cocanougher Short, BSN, MS, for helpful comments; Rima Farhat Maghes and Jennifer Jennings for manuscript preparation; Suzanne Simpson for editorial assistance; and Frederick L. Dunn, MD, and Tommie Friday for their continued support to make the Registry a reality. Appendix: The following institutions and investigators are psrticipants in the Heart Transplant Lipid Registry: University of Alabama in Birmingham, Birmingham, Alabama: Robert C. Bourge, MD; Baylor College of Medicine, Houston, Texas: Christie M. Ballantyne, MD, Jerry Levi, MD, John A. Farmer, MD, and Beth CocanougherShort, BSN, MS; The Cleveland Clinic Foundation, Cleveland, Ohio: JamesB. Young, MD; Duke University, Durham, North Carolina: Leslie Dornalik, MD; The Minneapolis Heart Institute, Abbott Northwest Hospital, Minneapolis, Minnesota: Kathleen D. Lake, PharmD, BCPS; University of Minnesota at Minneapolis-St. Paul, Minneapolis, Minnesota: Spencer H. Kubo, MD; The Ochsner Clinic, New Orleans, Louisiana: Hector 0. Ventura, MD; University of Texas Southwestern Medical Center, Dallas, Texas: Clyde W. Yancy, MD; Temple University, Philadelphia, Pennsylvania: Howard .I. Eisen, MD: The Texas Heart Institute, Houston, Texas: Branislav Radovancevic, MD: University of Utah, Salt Lake City, Utah: David 0. Taylor, MD, University of Washington, Seattle,Washington: Daniel P. Fishbein, MD, and Kevin O’Brien, MD. 1. Hosenpud J, Novick RJ, Breen TJ, Keck B, Daily P. The registration of the international society for heart and lung transplantation: twelfth official report. J Heart Lung Transplant 1995;14:805-815. 2. Uretsky BF, Murali S, Reddy PS, Rabin B, Lee A, Griffith BP, Hardesty RL, Trento A, BahnsonHT. Development of coronary artery diseasein cardiac transplant patients receiving immunosuppressive therapy with cyclosporine and prednisone. Circ&tion 1987;76:827-834. 3. Scandinavian Simvastatin Survival Study Group. Randomised hial of cholesterol lowering in 4444 patients with coronary heart disease:the Scandinavian Simvastatin Survival Study (4s). Lancer 1994;344:1383-1389. 4. Gotto AM. Lipid lowering, regression, and coronary events. Circulation 1995;92:646-656. 5. National Cholesterol Education Program. Secondreport of the expert panel on detections, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel II) Circulation 1994;89:1329-1445. 6. Ballantyne CM, Jones PH. Payton-Ross C, PatschW, Short HD, Noon GP, Gotto AM, DeBakey MB, Young JB. Hyperlipidemia following heart transplantation: natural history and intervention with mevinolin (lovastatin). Transp Proc 1987;19(5):60-62. 7. Keogh A, Simons L, Spratt P, Esmore D, Chang V, Hickie J, Baron D. Hyperlipidemia after heart transplantation. J Heart Lung Transplanr 1988;7:171-175. 8. Ballantyne CM, Radovancevic B, Farmer JA, Frazier OH, Chandler L, Payton-Ross C, CocanougherB, JonesPH. Young JB, Gotto AM. Hyperlipidemia after heart transplantation: report of a 6-year experience. with treatment recommendations.JAm CoZCardiol 1992;19:1315-1321. 9. Hess ML, Hastillo A, Mohanakumar T, Cowley MI, Vetrovac G, Szentpetety S, Wolfgang TC, Lower RR. Accelerated atherosclerosis in cardiac transplantation: role of cytotoxic B-cell antibodies and hyperlipidemia. Circularion 1983;68:11-94-101. 10. Eich D, Thompson JA, Ko D, Hastillo A, Lower R, Katz S, Katz M, Hess ML. Hypercholesterolemia in long-term survivors of heart transplantation: An early marker of accelerated coronary artery disease. J Heart Lung Transplanr 1991;10:45-49. 11. Gao S-Z, SchroederJS. Alderman EL, Hunt SA, Silverman JF, Wiederhold V, Stinson EB. Clinical and laboratory correlates of acceleratedcoronary artery diseasein the cardiac transplant patient. Circulation 1987;76:V-56-61.
12. Cocanougher B, Ballantyne CM, Pollack MS, Payton-Ross C, Lowry R, Kleiman NS, Farmer JA, NoOn GP, Short HD, Young JB. Degree of HLA mismatch as a predictor of death from allograft arteriopathy after heart transplant. Transp Proc 1993;25:233-236. 13. Mehra MR. Ventura HO, ChambersR, Collins TJ, Ramee SR, Kates MA, Smart FW, Stapleton DD. Predictive model to assessrisk for cardiac allograft vasculopathy: an intravascular ultrasound study. J Am Coil Cardiol 1995;26:1537-1544. 14. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol Education Program(NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II). JAMA 1993;269:3015-3023. 15. Kobashigawa JA, Katznelson S, Laks H, Johnson JA, Yeatman L, Wang XM, Cbia D, Terasaki PI, Sabad A, Cogert GA, Trosian K, Hamilton MA, Moriguchi ID, Kawata N, Hage A, Drinkwater DC, Stevenson LW. Effect of pravastatin on outcomes after cardiac transplantation. N Engl J Med 1995;333:621-627. 16. Cutts JL, Bankhurst AD. Reversal of lovastatin-mediated inhibition of natural killer cell cytotoxicity by interleukin 2. J Cell Physiol 1990,145:244-252. 17. Awni WM, Heim-Duthoy K, Kasiske BL. Impact of lipoproteins on cyclosporine pharmacokinetics and biological activity in transplant patients. Transp Proc 1990;22:1193-1196. 18. Meiser BM, Wenke K. Thiery J, Wolf S, Devens CH, Seidel D, Hammer C, Billingham ME, Reichart B. Simvastatin decreasesaccelerated graft vessel disease after heart transplantation in an animal model. Transp Proc 1993;25:2077-2079. 19. Vincent TS, Wulfert E, Merler E. Inhibition of growth factor signaling pathways by lovastatin. Rio&em Siophy Res Comm 1991;180:1284-1289. 20. Norman DJ, Illingworth DR, Munson J, Hosenpud J. Myolysis and acute renal failure in a heart-transplant recipient receiving lovastatin. N Engl J Med 1988;318:46-47. 21. Kobashigawa JA, Murphy FL, Stevenson LW, Moriguchi JD, Kawata N, Kamjoo P, Brownfield E, Wilmarth J, Leonard L, Chuck C, Drinkwater D, Laks H. Low-dose lovastatin safely lowers cholesterol after cardiac transplantation. Circulation 1990;82:IV-281-283. 22. Bradford RH, Shear CL, Cbremos AN et al. Expanded clinical evaluation of lovastatin (EXCEL) study results: I. Efficacy in modifying plasma lipoproteins and adverse event profile in 8245 patients with moderate hypercholesterolemia. Arch Intern Med 1991;151:43-49. 23. Kuo PC, KirshenbaumJM, Gordon J, Laffel G, Young P, DiSesaVJ, Mudge GH, Vaughan DE. Lovastatin therapy for hypercholesterolemiain cardiac tmnsplant recipients. Am J Cardiol 1989;64:631-635. 24. PetersJR, Kubo SH, Olivari MT, Knutson KR, HunninghakeDB. Treatment of hyperlipidemia in heart transplant recipients with gemfibrozil + lovastatin. Am J Cardiol 1993;71:1485-1488. 25. Anguita M, Alonso-Pulpon L, Arizon JM, Cavero MA, Valles F, Segovia J, Perez-JimenezF, Crespo M, Concha M. Comparison of the effectiveness of lovastatin therapy for hypercholesterolemia after heart transplantation between patients with and without pretransplant atherosclerotic coronary artery disease. Am J Cardiol 1994;74:776-779.
26. Hidalgo L, Zambrana JL, Blanco-Molina A, Lopez-Granados A, Concha M, CasaresJ, Perez-JimenezF. Lovastatin versus bezatibrate for hyperlipemia treatment after heart transplantation. J Heart Lung Transplant 1995;14:461467. 27. Barbir M, Rose M, Kushwaha S, Akl S, Mitchell A, Yacoub M. Low-dose
simvastatin for the treatment of hypercholesterolemia in recipients of cardiac transplantation. Int J Cardiol 1991;33:241-246. 28. VanhaeckeJ, Van Cleemput J, Van Lierde J, DaenenW, De GeestH. Safety and efficacy of low dose simvastatin in cardiac eansplant recipients treated with cyclosporine. Transplantation 1994;58:42-45. 29. CampanaC, Iacona 1, Regazzi MB, Gavazzi A, Perani G, Raddato V, Montemartini C, Vigano M. Efficacy and pharmacokinetics of simvastatin in heart transplant recipients. Ann Pharmacorher 1995;29:235-239. 30. Pflugfelder PW, Huff M, O&Ins R, Rudas L, Kostuk WJ. Cholesterollowering therapy after heart transplantation: a 1Zmonth randomized trial. J Heart Lung Transplanr 1995;14:613-622. 31. Regazzi MB, lacona I, CampanaC, Gavazzi A, Vigano M, Perani G. Clinical efficacy and pharmacokinetics of HMG-CoA reductaseinhibitors in heart transplant patients treated with cyclosporine A. Transp Proc 1994;26:264& 2645. 32. Smith PF, Eydelloth RS, GrossmanSJ, StubbsRJ, Schwartz MS, Germers-
hausenJI, Vyas KP, Kari PH, Macdonald JS. HMG-CoA reductase inhibitorinduced myopathy in the rat: cyclosporine A interaction and mechanismstudies. J Pharmacol Exp Ther 1991;257:1225-1235.
33. Goldberg RB, Roth D. A preliminary report of the safety and efficacy of fluvastatin for hypercholesterolemia in renal transplant patients receiving cyclosporine. Am J Cardiol 1995;76:107A- 109A. 34. Henkin Y, Oberman A, Hurst DC, Segrest JP. Niacin revisited: clinical observations on an important but underutilized drug. Am J Med 1991;91:239246.
PREVENTIVE CARDIOLOGY/HEART
TRANSPlANT LIPID REGISTRY 535
normal plus muscle symptoms. One randomized, controlled prospective trial has investigated the effects of lipid-lowering pharmacotherapy on patient outcome in cardiac transplant recipients. At 1-year follow-up in this nonblinded, single-center trial, patients treated with pravastatin (20 or 40 mg/day) initiated within 2 weeks of transplantation had a significant reduction in mortality rate and a significantly lower incidence of transplant arteriopathy. A number of important issues remain unanswered regarding treatment guidelines in patients with hyperlipidemia after heart transplantation. In January 1995 we began the Heart Transplant lipid Registry, with 12 participant centers, to gather data prospectively on the efficacy and safety of lipid-lowering drugs in the treatment of dyslipidemia after heart transplantation. (Am J Cardiol 1996;78:532-535)
ore than 30,000 cardiac transplants have been M reported to the Registry of the International Society for Heart and Lung Transplantation since
solved questions concerning practical therapeutic issues, and presents the rationale for the recently instituted Heart Transplant Lipid Registry.
1983; almost 3,000 were performed in 1994.’ With increasing numbers of heart transplants and improved l-year survival rates, more patients face the problem of accelerated atherosclerotic coronary artery disease (CAD), the leading cause of morbidity and mortality among those surviving > 1 year.* Treatment of hyperlipidemia in patients with CAD has been shown to slow lesion progression and to reduce CAD morbidity along with both CAD and all-cause mortality rates.3*4 The adult treatment guidelines of the National Cholesterol Education Program’ emphasize CAD risk status as a guide to the intensity of lipid-lowering therapy. Individuals with the greatest probability of having a CAD event within the next 5 to 10 years are candidates for the most aggressive intervention. The guidelines, however, do not specifically address management of hyperlipidemia in heart transplant recipients. This article reviews the available data on treatment of hyperlipidemia in these patients, discusses unreFrom the Section of Atherosclerosis, Department of Medicine, Baylor College of Medicine, Houston, Texas, on behalf of the Heart Transplant Lipid Registry. This work was supported by a grant from Merck and Co., Inc, West Point, Pennsylvania. Manuscript received December 15, 1995; revised manuscript received and accepted March 22, 1996. Address for reprints: Christie M. Ballantyne, MD, Department of Medicine, MS A-601, Baylor College of Medicine, 6565 Fannin Street, Houston, Texas 77030.
532
0 1996 by Excerpta Medica, All riahts reserved.
Inc.
SCOPE OF THE PROBLEM Many studies have clearly documented that hyperlipidemia is common after heart transplantation.6*7 In 1 series, low-density lipoprotein (LDL) cholesterol remained 2130 mg/dl in 64% of patients; plasma triglyceride remained 2200 mg/dl in 41% of patients 6 months after postoperative dietary instruction*; and more than 85% of patients had LDL cholesterol 2 100 mg/dl despite dietary therapy. The high frequency of hyperlipidemia is clearly multifactorial and related to immunosuppressive therapy, weight gain, and previous history of hyperlipidemia. Cyclosporine has been shown to increase LDL cholesterol concentrations significantly. The frequency of transplant arteriopathy varies widely among studies, which may reflect either differences in methods of detection or true variations in incidence among centers due to differences in medical management. Multiple studies-most commonly, retrospective analyses of data from single institutions-have examined risk factors for transplant arteriopathy. The studies have varied in the risk factors evaluated, follow-up period, and definition of CAD, and results have been conflicting. Nevertheless, the cumulative data suggest that the development of transplant CAD is influenced by both immune and nonimmune factors. Although a relation 0002-9149/96/Q 15.00 PII 50002-9149(96)00358-X
with hyperlipidemia has been demonstrated by multiple studies, some have shown a correlation with elevations of total or LDL cholesterol,9~10others with plasma triglyceride, ’ l-l3 and yet others have found no correlation with either cholesterol or triglyceride.* In animal models, however, hyperlipidernia consistently accelerates the development of allograft arteriopathy. It is highly probable that hyperlipidemia plays a role in the development of CAD after transplantation, but it is difficult to estimate its relative contribution to the risk.
BENEFITS AND RISKS OF UPIDLOWERING DRUG THERAPY AFTER HEART TRANSPLANTATION Guidelines for lipid-lowering drug therapy have been formulated to optimize its benefits while minimizing its risks. Long-term randomized clinical trials have shown clear benefit from drug therapy in both patients with and without symptomatic CAD.14 The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) and nicotinic acid have been key agents in multiple secondary prevention trials, and benefit in healthy patients has been achieved with a resin, a fibrate, or a statin. In contrast to this wealth of data, only 1 randomized, controlled prospective trial has investigated the effects of lipid-lowering pharmacotherapy on outcome in cardiac transplant recipients. At l-year follow-up in this nonblinded, single-center trial, patients treated with pravastatin (20 or 40 mg/day, initiated within 2 weeks of transplantation; n=47) had a significant reduction in mortality rate, as well as a significantly lower incidence of transplant arteriopathy, as assessed by angiography and at autopsy, and significantly less lesion progression, as determined by intracoronary ultrasound.‘5 The pravastatin group also had significant reductions in hemodynamically significant rejection and natural killer cell cytotoxicity. There are several potential mechanisms whereby pravastatin may have caused an increased state of immunosuppression in this study. Statins have been shown to decrease antibodydependent cellular cytotoxicity and natural killer cell function.16 In addition, marked reductions in plasma lipoprotein concentrations might influence cyclosporine activity. The majority of cyclosporine in plasma is bound, exclusively, to lipoproteins. A marked decrease in lipoprotein concentrations would lead to an increased proportion of free cyclosporine in plasma. The result could be significant increases in the biologic activity of cyclosporine, even with similar whole blood trough levels.” Statins may have direct vascular effects on intimal proliferation. Simvastatin has been shown to reduce allograft arteriopathy without significant changes in lipoprotein concentrations in a rat model of heart transplantation with FK506 immunosuppressive therapy.” Inhibition of mevalonate products, such as famesyl-PP and geranyl-PP, by statins could inhibit cellular proliferation. l9
The low incidence of adverse side effects with lipid-lowering drug therapy in patients with native CAD has been clearly established in large, multicenter prospective trials, which have included many thousands of patient-years of follow-up.3,4 Risk for toxicity from lipid-lowering drugs is increased in transplant patients receiving cyclosporine and prednisone. The initial, enthusiastic report6 of post-transplantation lipid lowering using lovastatin at a high dosage (80 mg/day) was followed by reports of rhabdomyolysis.8S20It was found that 3-hydroxy-3methylglutaryl coenzyme A reductase inhibitory activity in plasma is markedly increased in patients given lovastatin in conjunction with cyclosporine and prednisone.8%21 The hypothesis that elevation of plasma concentrations of lovastatin and its (active) metabolites, owing to an interaction with immunosuppressive drugs, might be a mechanism for myopathy was further supported by a large prospective trial** that examined the safety of lovastatin therapy in hypercholesterolemic patients not receiving immunosuppressive therapy. The incidence of rhabdomyolysis-which was defined as creatine kinase elevation > 10 times the upper limit of normal with muscle symptoms-was dose dependent, varying from 0.02% ( l/4,933 patients) for dosages ~40 mg/ day to 0.24% (4/1,649 patients) at 80 mg/day.22 Administration of lovastatin concomitant with gemfibrozil, nicotinic acid, erythromycin, or itraconazole also increased the risk for rhabdomyolysis. Caution should be used in administering other drugs metabolized by the cytochrome P450 system (for example, macrolide antibodies, calcium channel blockers) to patients receiving both cyclosporine and a statin. Since the initial reports in the 1980s of rhabdomyolysis in heart transplant patients receiving high dosages of lovastatin, results of 11 post-transplantation series that used lovastatin, 8~21~23-*6 simvastatin, 27-30or pravastatin l5 as drug monotherapy have been published (Table I). These studies have shown a much lower incidence of rhabdomyolysis (defined as creatine kinase > 10 times the upper limit of normal with muscle symptoms) : lovastatin 1.l% (2/ 186)) simvastatin 1.4% ( l/7 1) , and pravastatin 0% (O/47), or 1.01% (3/304) overall. Unfortunately, the studies had limited follow-up periods and small numbers of patients, and all were from single centers. The four available statins-lovastatin, simvastatin, pravastatin, and (the most recently approved) fluvastatin-differ in pharmacokinetic profile with respect to hydrophilicity, first-pass extraction by the liver, plasma half-life, and protein binding. Pharmacokinetic studies have shown that cyclosporine interacts not only with lovastatin 21and simvastatin, 31 which are lipophilic, but also with pravastatin, which is more hydrophilic. In heart transplant recipients, coadministration of cyclosporine altered the disposition of pravastatin, including a 20-fold increase in the area under the curve and a I-/-fold increase in maximum plasma concentration (C,,,) .31 In rats treated with lovastatin, simvastatin, or pravastatin, coadministration of cyclosporine resulted in in-
PREVENTIVE CARDIOLOGY/HEART
TRANSPLANT LIPID REGISTRY 533
TABLE I Recent Clinical
Studies of SingleAgent Doily Dose
Study Kuo et al, 198923 Koboshigawa et al, 1 9902’ Ballantyne et al, 1992’ Peters et 01, 199324 Anguita et al, 1994= Hidalgo et al, 1 99526 Barbiretal,19912’ Vanhaecke et 01, 1 99428 Campano et al, 1 99429 Pflugfelder et al, 1 99530 Kobashigawa et al, 1 9951S
Statin Therapy
After Heart Transplantation
Follow-up ATG%
AHDL%
Myositis/ Myalgias
Rhabdomyolysis: lOxCK+ Symptoms
Drug
(msl
n
b-4
TC%
ALDL%
L L
20-60 10-20
11 44
15 (3-41) zz6
-27 -26
-34 -26
+5 -22
+5 -2
0 NR
L
20
15
13 (6-30)
-21
-31
-8
+8
1
0
1 1
20 lo-40
35 63
NR 13
-24 -15
NR -21
-5 -17
NR +3
0 2
L
10
18
2
-15
-21
-2
-2
1
0 1 (believed 2” to colchicine) 0
S S
10 5-15
12 26
8 12
-38 -27
-42 -40
-25 -21
+9 -2
0 0
0 1 (at 15 mg)
S
10
20
4
-12.5
-21.3
+lO
0
0
S
10
13
12
-24
-39
-21
+2
0
0
P
20-40
47
12
-22*
-27’
-32*
+21*
0
0
-4
0 1 (at 40 mg)
l Compared with control group (n = 50) rather than baseline value. CK = creatine kinare; HDL = highdensity lipoprotein cholesterol; 1 = lovastatin; LDL = lowdensity lipoprotein cholesterol; NR = not reported; P = pravastotin; S = simvastatin; TC = total cholesterol; TG = triglyceride; A = change.
creased systemic exposure, with a consequent increase in myopathy for each statin. No study using fluvastatin after heart transplantation has yet been published, although use for 14 weeks in 19 renal transplant recipients led to an asymptomatic increase in creatine kinase > 10 times the upper limit of normal in 1 patient.33 Although nicotinic acid has beneficial effects in mixed hyperlipidemia, which is frequently seen after heart transplantation, 65% of the heart transplant recipients in 1 study were unable to tolerate the agent because of adverse effects such as impaired glucose tolerance 34The bile acid-binding resins may interfere with’absorption of lipid-soluble drugs, such as cyclosporine, and also may raise plasma triglyceride concentrations. The fibrate gemfibrozil is well tolerated in heart transplant patients and leads to marked reductions in triglycerides.” However, reductions in total and LDL cholesterol concentrations are both more modest and variable, limiting treatment of severe hypercholesterolemia that often occurs after heart transplantation.*
1. What lipid values should be used as thresholds for initiation of drug therapy, and what should the lipid goals be? Should goals be based on LDL cholesterol alone or, on the basis of available clinical data, should plasma triglyceride also be considered? Should all patients receive lipid-lowering drug treatment regardless of lipid values? 2. When should drug therapy be initiated? In a recent study that showed benefits in transplant arteriopathy,” therapy was initiated 1 to 14 days after transplantation. Would waiting 6 to 12 weeks to assess lipid changes in patients on dietary therapy be less effective? 3. How much change in lipoprotein concentrations can be achieved by the available agents, and with how much toxicity? What factors predispose to the development of myopathy? 4. What is the relation between therapeutically induced changes in lipoprotein concentrations and clinical end points such as development of arteriopathy, rejection episodes, and all-cause mortality? 5. Are there clinically significant differences among the statins with regard to efficacy and safety? 6. What is the most cost-effective way to treat UNRESOLVED QUESTIONS If both immune and nonimmune risk factors are hyperlipidemia in heart transplant recipients? important in the development of transplant CAD, FOR THE HEART what reductions in morbidity and mortality from RATIONALE LIPID REGISTRY transplant CAD could theoretically be achieved with TRANSPLANT In January 1995, we began the Heart Transplant optimal lipid-lowering therapy? Although a clear answer to this question would require a large, multi- Lipid Registry, involving 12 centers, to gather procenter trial, the results of a single, prospective trial l5 spective data on the efficacy and safety of lipid-lowindicate that the benefit could be considerable. ering drugs in the treatment of dyslipidemia after Therefore, we would like to pose a number of im- heart transplantation. The registrjr is designed to corportant questions regarding drug treatment guide- relate information on the treatment of hundreds of lines in patients with hyperlipidemia after heart transplant recipients, with thousands of patient-years of follow-up, to provide a clearer picture of the litransplantation: 534
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78
SEPTEMBER
1, 1996
poprotein changes achieved and the incidence of serious adverse effects. The data should be helpful for the design of larger, multicenter prospective trials, to address more definitively the question of the optimal treatment of dyslipidemia in heart transplant recipients for the reduction of morbidity and mortality from transplant arteriopathy. Furthermore, the data may also be useful in assessment of the most cost-effective way to treat dyslipidemia in this patient population. Acknowledgments: We thank Alistair Fyfe, MD, PhD, Evan Stein, MD, PhD, and Beth Cocanougher Short, BSN, MS, for helpful comments; Rima Farhat Maghes and Jennifer Jennings for manuscript preparation; Suzanne Simpson for editorial assistance; and Frederick L. Dunn, MD, and Tommie Friday for their continued support to make the Registry a reality. Appendix: The following institutions and investigators are psrticipants in the Heart Transplant Lipid Registry: University of Alabama in Birmingham, Birmingham, Alabama: Robert C. Bourge, MD; Baylor College of Medicine, Houston, Texas: Christie M. Ballantyne, MD, Jerry Levi, MD, John A. Farmer, MD, and Beth CocanougherShort, BSN, MS; The Cleveland Clinic Foundation, Cleveland, Ohio: JamesB. Young, MD; Duke University, Durham, North Carolina: Leslie Dornalik, MD; The Minneapolis Heart Institute, Abbott Northwest Hospital, Minneapolis, Minnesota: Kathleen D. Lake, PharmD, BCPS; University of Minnesota at Minneapolis-St. Paul, Minneapolis, Minnesota: Spencer H. Kubo, MD; The Ochsner Clinic, New Orleans, Louisiana: Hector 0. Ventura, MD; University of Texas Southwestern Medical Center, Dallas, Texas: Clyde W. Yancy, MD; Temple University, Philadelphia, Pennsylvania: Howard .I. Eisen, MD: The Texas Heart Institute, Houston, Texas: Branislav Radovancevic, MD: University of Utah, Salt Lake City, Utah: David 0. Taylor, MD, University of Washington, Seattle,Washington: Daniel P. Fishbein, MD, and Kevin O’Brien, MD. 1. Hosenpud J, Novick RJ, Breen TJ, Keck B, Daily P. The registration of the international society for heart and lung transplantation: twelfth official report. J Heart Lung Transplant 1995;14:805-815. 2. Uretsky BF, Murali S, Reddy PS, Rabin B, Lee A, Griffith BP, Hardesty RL, Trento A, BahnsonHT. Development of coronary artery diseasein cardiac transplant patients receiving immunosuppressive therapy with cyclosporine and prednisone. Circ&tion 1987;76:827-834. 3. Scandinavian Simvastatin Survival Study Group. Randomised hial of cholesterol lowering in 4444 patients with coronary heart disease:the Scandinavian Simvastatin Survival Study (4s). Lancer 1994;344:1383-1389. 4. Gotto AM. Lipid lowering, regression, and coronary events. Circulation 1995;92:646-656. 5. National Cholesterol Education Program. Secondreport of the expert panel on detections, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel II) Circulation 1994;89:1329-1445. 6. Ballantyne CM, Jones PH. Payton-Ross C, PatschW, Short HD, Noon GP, Gotto AM, DeBakey MB, Young JB. Hyperlipidemia following heart transplantation: natural history and intervention with mevinolin (lovastatin). Transp Proc 1987;19(5):60-62. 7. Keogh A, Simons L, Spratt P, Esmore D, Chang V, Hickie J, Baron D. Hyperlipidemia after heart transplantation. J Heart Lung Transplanr 1988;7:171-175. 8. Ballantyne CM, Radovancevic B, Farmer JA, Frazier OH, Chandler L, Payton-Ross C, CocanougherB, JonesPH. Young JB, Gotto AM. Hyperlipidemia after heart transplantation: report of a 6-year experience. with treatment recommendations.JAm CoZCardiol 1992;19:1315-1321. 9. Hess ML, Hastillo A, Mohanakumar T, Cowley MI, Vetrovac G, Szentpetety S, Wolfgang TC, Lower RR. Accelerated atherosclerosis in cardiac transplantation: role of cytotoxic B-cell antibodies and hyperlipidemia. Circularion 1983;68:11-94-101. 10. Eich D, Thompson JA, Ko D, Hastillo A, Lower R, Katz S, Katz M, Hess ML. Hypercholesterolemia in long-term survivors of heart transplantation: An early marker of accelerated coronary artery disease. J Heart Lung Transplanr 1991;10:45-49. 11. Gao S-Z, SchroederJS. Alderman EL, Hunt SA, Silverman JF, Wiederhold V, Stinson EB. Clinical and laboratory correlates of acceleratedcoronary artery diseasein the cardiac transplant patient. Circulation 1987;76:V-56-61.
12. Cocanougher B, Ballantyne CM, Pollack MS, Payton-Ross C, Lowry R, Kleiman NS, Farmer JA, NoOn GP, Short HD, Young JB. Degree of HLA mismatch as a predictor of death from allograft arteriopathy after heart transplant. Transp Proc 1993;25:233-236. 13. Mehra MR. Ventura HO, ChambersR, Collins TJ, Ramee SR, Kates MA, Smart FW, Stapleton DD. Predictive model to assessrisk for cardiac allograft vasculopathy: an intravascular ultrasound study. J Am Coil Cardiol 1995;26:1537-1544. 14. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol Education Program(NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II). JAMA 1993;269:3015-3023. 15. Kobashigawa JA, Katznelson S, Laks H, Johnson JA, Yeatman L, Wang XM, Cbia D, Terasaki PI, Sabad A, Cogert GA, Trosian K, Hamilton MA, Moriguchi ID, Kawata N, Hage A, Drinkwater DC, Stevenson LW. Effect of pravastatin on outcomes after cardiac transplantation. N Engl J Med 1995;333:621-627. 16. Cutts JL, Bankhurst AD. Reversal of lovastatin-mediated inhibition of natural killer cell cytotoxicity by interleukin 2. J Cell Physiol 1990,145:244-252. 17. Awni WM, Heim-Duthoy K, Kasiske BL. Impact of lipoproteins on cyclosporine pharmacokinetics and biological activity in transplant patients. Transp Proc 1990;22:1193-1196. 18. Meiser BM, Wenke K. Thiery J, Wolf S, Devens CH, Seidel D, Hammer C, Billingham ME, Reichart B. Simvastatin decreasesaccelerated graft vessel disease after heart transplantation in an animal model. Transp Proc 1993;25:2077-2079. 19. Vincent TS, Wulfert E, Merler E. Inhibition of growth factor signaling pathways by lovastatin. Rio&em Siophy Res Comm 1991;180:1284-1289. 20. Norman DJ, Illingworth DR, Munson J, Hosenpud J. Myolysis and acute renal failure in a heart-transplant recipient receiving lovastatin. N Engl J Med 1988;318:46-47. 21. Kobashigawa JA, Murphy FL, Stevenson LW, Moriguchi JD, Kawata N, Kamjoo P, Brownfield E, Wilmarth J, Leonard L, Chuck C, Drinkwater D, Laks H. Low-dose lovastatin safely lowers cholesterol after cardiac transplantation. Circulation 1990;82:IV-281-283. 22. Bradford RH, Shear CL, Cbremos AN et al. Expanded clinical evaluation of lovastatin (EXCEL) study results: I. Efficacy in modifying plasma lipoproteins and adverse event profile in 8245 patients with moderate hypercholesterolemia. Arch Intern Med 1991;151:43-49. 23. Kuo PC, KirshenbaumJM, Gordon J, Laffel G, Young P, DiSesaVJ, Mudge GH, Vaughan DE. Lovastatin therapy for hypercholesterolemiain cardiac tmnsplant recipients. Am J Cardiol 1989;64:631-635. 24. PetersJR, Kubo SH, Olivari MT, Knutson KR, HunninghakeDB. Treatment of hyperlipidemia in heart transplant recipients with gemfibrozil + lovastatin. Am J Cardiol 1993;71:1485-1488. 25. Anguita M, Alonso-Pulpon L, Arizon JM, Cavero MA, Valles F, Segovia J, Perez-JimenezF, Crespo M, Concha M. Comparison of the effectiveness of lovastatin therapy for hypercholesterolemia after heart transplantation between patients with and without pretransplant atherosclerotic coronary artery disease. Am J Cardiol 1994;74:776-779.
26. Hidalgo L, Zambrana JL, Blanco-Molina A, Lopez-Granados A, Concha M, CasaresJ, Perez-JimenezF. Lovastatin versus bezatibrate for hyperlipemia treatment after heart transplantation. J Heart Lung Transplant 1995;14:461467. 27. Barbir M, Rose M, Kushwaha S, Akl S, Mitchell A, Yacoub M. Low-dose
simvastatin for the treatment of hypercholesterolemia in recipients of cardiac transplantation. Int J Cardiol 1991;33:241-246. 28. VanhaeckeJ, Van Cleemput J, Van Lierde J, DaenenW, De GeestH. Safety and efficacy of low dose simvastatin in cardiac eansplant recipients treated with cyclosporine. Transplantation 1994;58:42-45. 29. CampanaC, Iacona 1, Regazzi MB, Gavazzi A, Perani G, Raddato V, Montemartini C, Vigano M. Efficacy and pharmacokinetics of simvastatin in heart transplant recipients. Ann Pharmacorher 1995;29:235-239. 30. Pflugfelder PW, Huff M, O&Ins R, Rudas L, Kostuk WJ. Cholesterollowering therapy after heart transplantation: a 1Zmonth randomized trial. J Heart Lung Transplanr 1995;14:613-622. 31. Regazzi MB, lacona I, CampanaC, Gavazzi A, Vigano M, Perani G. Clinical efficacy and pharmacokinetics of HMG-CoA reductaseinhibitors in heart transplant patients treated with cyclosporine A. Transp Proc 1994;26:264& 2645. 32. Smith PF, Eydelloth RS, GrossmanSJ, StubbsRJ, Schwartz MS, Germers-
hausenJI, Vyas KP, Kari PH, Macdonald JS. HMG-CoA reductase inhibitorinduced myopathy in the rat: cyclosporine A interaction and mechanismstudies. J Pharmacol Exp Ther 1991;257:1225-1235.
33. Goldberg RB, Roth D. A preliminary report of the safety and efficacy of fluvastatin for hypercholesterolemia in renal transplant patients receiving cyclosporine. Am J Cardiol 1995;76:107A- 109A. 34. Henkin Y, Oberman A, Hurst DC, Segrest JP. Niacin revisited: clinical observations on an important but underutilized drug. Am J Med 1991;91:239246.
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