- Email: [email protected]
Treatment of hyperlipidemia in heart transplant recipients with gemfibrozil ± lovastatin
reatment of Hyperlipidemi Gemfibrozil f Lovastatin
eart Transplant Recipients with
Jeffrey R. Peters, MA, MPH, Spencer 11.Kubo, MD, Maria Teresa Olivari. MD. Kevin I?, Krllts:nl?, nc, alid ihlaid 3. hnnlngtlake, WI mprovements in the diagnosis and therapy of early rejection and infection have resulted in 30% l-year survival for heart transplant recipients.’ However, accelerated coronary vasculopathy is a frequent long-term complication and is the cause of death in up to 20% of patients followed >l year,l” with some degree of vasculopathy noted in all autopsy examinations.4J Hypercholesterolemia,a frequent complication of heart transplantation, appears to be associated with accelerated coronary disease. 3&8 Severalrecent studies have demonstratedthat reducing plasma cholesterol can decreasethe development and the progression of atherosclerosis in both native coronary arteries and bypass grafts.9-11 Based on these factors, there have been several reports on the use of hypolipidemic drugs in heart transplant recipients.12,i3These studies usually involved only a small number of patients and only 1 drug. We therefore retrospectively examinedchangesin lipid values in 71 heart transplant recipients who received drug therapy for hyperlipidemia that was primarily guided by a step-care approach involving gemjibrozil in 2 doses, followed by lovastatin for more resistant cases. From December1983 through August 1991,164 adults (>I8 years of age) underwentheart transplantation at the University of Minnesotaand survived at least I year. From this group, drug therapy was initiated in 71 patients with cholesterollevels that were consistently >240 mgldl, and From the Heart Disease Prevention Clinic and Cardiovascular Division, University of Minnesota Medical School, Minneapolis, Minnesota. Mr. Peters’ address is: Heart Disease Prevention Clinic, Department of Medicine, Box 192, University of Minnesota Hospital and Clinics, University of Minnesota, 401 East River Parkway, Minneapolis, Minnesota 55455. Manuscript received October 13, 1992; revised manuscript received January 4, 1993, and accepted January 5.
thesepatients were entered into this retrospectiveinvestigation. The previous diagnosis of coronary artery disease in 53 (75%) ana! idiopathic cardiomyopathyin 18 (25%) is somewhatdyerent than the international average of50 and 40%, respectively.The time course of lipid changes and the risk factors in$uencing the developmentof hypercholesterolemia in this cohort of patients has been described in an earlier report.14 Tripb-drug immunosuppression15included oral cyclosporine at 2 to 6 mglkglday in 2 divided doses adjusted to maintain a whole blood trough level of 200 nglml for the first 6 months and 100 nglml thereafter. Azathioprine doses were maintained at 2.5 mglkglday with adjustments to maintain a white blood cell count >4000 mm3. Oral prednisone (1 mglkglday) was tapered to 0.3 mglkglday by 3 months and 0.1 mglkglday by 12 months. tIj?er transplant, all patients were instructed on the importance of weight control, exercise, and a low-fat, low-cholesterol diet, but compliance to these lifestyle recommendations was not strictly monitored. Blood pressure, weight and blood chemistries were obtained at most visits. Plasma cholesterol and triglycerides were measured every 3 months using standard Lipid Research Clinics techniques.16Patients receiving lovastatin were monitored jbr creatine kinase elevations after thefirst 2 weeksand then every 3 months. Lipoproteins, low-density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol were not perjormed routinely in the early phases of this study. Thus, paired comparisons of the responseof lipoprotein fractions to transplantation, weight gain or drug therapy are not included. Therapy was initiated with gemfibrozil(600 mglday) in most patients with total plasma cholesterol levels
Started on aemfibrozll
*
Swltched lovastatln
to
n=FJ
-
I200
mg/day
n-37 Remained on 600 mg/day n=7
steps taken by patients iscussion, see text.
drug Or ment in the s&My. For
to
Switched lovastatfn il=5
to
4 Remained on 1200 mg/day n=22 Started
ALL PATIENTS N=7 I
SwItched lovaktatln n=15
on ---+B-
Started on lovastatln n-7
BRIEFREPORTS
X40 mgldl (n = 52, Figure 1). A response was dejned as a reduction in plasma cholesterol to 1240 mgldl or by 210% from post-transplant baseline. If this response was not obtained, the dose of gemfibrozil was increased to 1,200 mglday. For those who did not respond to the higher dose of gemjibrozil, therapy was changed to lovastatin (20 mglday). Somepatients did not follow each station of this step-care approach and bypassed gem@ brozil at the low dose (n = 12), the high dose (n = 8) or both doses (n = 7) before starting lovastatin. All values are reported as mean + SE. Lipid levels before drug treatment were compared to drug treatment levels with paired t tests utilizing the CLINFO system,as were drug responsesbetween steps. A p value co.05 was considered significant. The study included 58 men and 13 women (mean age 50.4 + 1.2 years). After transplantation, total cholesterol increased from 206 + 8 to 289 + 4 mgldl, triglycerides increasedfrom 190 f 18 to 279 f 17 mgl TABLE I Responses
Cholesterol (mg/dl) All patients Responders* Nonresponderst Triglycerides (mg/dl) All patients Responders Nonresponders Weight (kg) All patients Responders Nonresponders
of Patients
to 600
mglday
TABLE II Responses of Patients to 1,200 mg/day of Gemfibrozil
of Gemfibrozil
No.
After Transplant
Gemfibrozil (600 mg/day)
%A
pValue
52 7 45
287 (4) 271 (10) 289 (5)
272 (7) 216 (9) 280 (7)
-5 -20 -3
52 7 45
268 (20) 259 (40) 270 (22)
236 (18) 157 (18) 248 (20)
-12 -39 -8
0.05 <0.05 NS
47 7 40
84 (2) 83 (7)
86 (2) 88 (6) 86 (2)
+3 +5 +2
84 (2)
dl, and weight increasedfrom 74.4 +_1.8 to 81.6 rt 1.8 kg (all p
Cholesterol (mg/dl) All patients* Responderst Nonresponders+ Triglycerides (mg/dl) All patients Responders Nonresponders Weight (kg) All patients Responders Nonresponders *Patients
iPatients who increased gemfibroril Values are expressed as mean i SE.
TABLE Ill
%A
pValue
291 (5) 281 (6) 305 (8)
266 (6) 247 (7) 293 (8)
-9 -12 -4
49 29 20
291(22) 320 (32) 248(24)
204 (15) 201 (21) 207 (22)
-30 -37 -17
41 22 19
81 (4) 80 (6) 82 (6)
85 (2) 84 (3) 87 (3)
increasingdosefrom
Responses of Patients to Lovastatin No.
After Transplant
35 15 8 5 7
299 301 281 317 305
(6) (9) (8) (14) (18)
227 224 210 216 262
35 15 8 5 7
236 235 225 287 212
(17) (27) (35) (46) (36)
225 236 204 230 221
32 15 6 4 7
82 83 86 82 79
(3) (3) (6) (5) (8)
Lovastatin %A
p Value
(7) (8) (8) (13) (25)
-24 -25 -25 -32 -14
(15) (27) 124) (22) (41)
-5 0
NS NS
-9 -20 +4
NS NS NS
(3) (3) (9) (8) (9)
+7 +lO -5 +5 +15
(20 mg/day)
88 90 82 86 91
*Patients stated on 600 mglday of gemfibrozil, titrated to 1,200 mglday, then switched TPatients started on 600 mgldayof gemfibrozil, then switched to lovastatm. ZPatients started on 1,200 mglday of gemfibrozil, then switched to lovastatin. §Patients whose initial therapy was lovastatin. Values are expressed as mean ? SE.
THE AMERICANJOURNALOF CARDIOLOGY VOLUME71
JUNE 15,1993
+5 +4 +6
600 mg (n = 37), plus those whose initial dose was
TPatients remaning on 1,200 mg/day of gemfibrozil. $Patients switching to lovastatin. Values are expressed as mean i SE.
to lovastatin.
Cholesterol (mg/dl) All patients Gemfibrozil 600, 1,200* Gemfibrozil 6007 Gemfibrozil 1,200$ Lovastating Triglycerides (mg/dl) All patients Gemfibrozil600, 1,200 Gemfibrozil 600 Gemfibrozil 1,200 Lovastatin Weight (kg) All patients Gemfibrozil 600, 1,200 Gemfibrozil 600 Gemfibrozil 1,200 Lovastatin
1486
49 29 20
Gemfibrozil (1,200
mg/day)
1,200 mg(n = 12).
*Patients who remained on 600 @day
gemflbrozil. dose or switched
No.
After Transplant
to lovastatin.
who demonstrated an inadequate response to 600 mglday (Table II); 12 patients received an initial dose of 1,200 mglday. For the entire group of 49 patients, total cholesterol decreasedby 25 mgldl (p
tions in cholesterol. Furthermore, gemfibrozil produced large reductions in triglycerides similar in magnitude to other gemtibrozil trials that reported only modest reductions in total cholesterol in mixed hyperlipidemias, but a 50% decreasein ~gty?~r&!es.~~ For those patients who switched to iovastatin, there were generally larger reductions in total cholesterol, averaging 24% for the total group. These responseswere similar to those reported in other studies in heart transplant recipients.r2,13However, in contrast to the response to gemfibrozil, there were usually only small reductions in triglycerides. Tobe@ and Corpier et all9 reported on the high risk of developing myopathy with high-dose lovastatin plus cyclosporine (up to 28% of patients). In this study, lovastatin was discontinued in 1 patient because of a moderate, but asymptomatic, increase in creaturekinase. The low frequency of myopathy with small doses of lovastatin in this study is in agreementwith other investigators.r2,13Thus, low-dose lovastati therapy appears to be well tolerated. Because there is a correlation between weight gain and lipid levels,2o it could be anticipated that there would be greater reductions in total cholesterol and triglycerides if weight had at least stabilized during postoperative follow-up. However, weight gain was observed in both respondersand nonrespondersand therefore was not correlated with cholesterol or triglyceride changes. Several additional factors could have affected the responsesto lipid-lowering therapy. Although instructions regarding low cholesterol, low saturated fat diets were provided for each patient, it is likely that variable compliance with these recommendations could have affected drug responses. There was no systematic taper of prednisone or cyclosporine in these patients, but it is possible that some patients were more sensitive to the hyperlipidemic effects of these drugs. Because this was a short-term study, the effects of treatment on the development of allograft vasculopathy and whether there are any important differencesbetween the drugs are not yet known. The examination of subgroup responsesrather than focusing on mean changes, highlights the heterogeneity of the therapeutic responses. From these data, we believe that a small percentage of patients will have a significant reduction in cholesterol with gemfibrozil alone. The cholesterol decreases with lovastatin will generally be larger, but the reduction in triglycerides will be less. Practitioners should be aware of the differencesin efficacy between these agents when considering hypolipidemic therapy in transplant patients, 1. k’ietl JM, Kaye MI’. The re@stq of the International Sociely for Heart and Lung Transplantation: eighth official report - 1991. JHeurt Lang Trarzsplant 1991; 10:49149x. 2. Uretsky BF, Murali S, Reddy PS, Rabin B, Lee A, Griffith BP, Hard&y RI,, Trento A, Bahnson m. Development of coronary artery discax in cardiac trans. plant patients receiving immunosuppressive therapy with cyclosporine aId pro&isane. Circulation 1987;76:827-834. 3. Babii M, Banner N, Thompson GR, Kbaghani A, Mitchell A, Yacoub M. Rdationship of inmmnosuppression and scmm lipids to the development of coronay arterial disease in the transplanted heart. lnt ./ Car&Z 1991;32:51-56. 4. Johnson DE, Gao Sz, Scbuxdcr JS, DeCampi WM, Billingham ME. The spectrum of coronary arlery pathology in human cardiac allografts. J Heart Transplant 1989;8:349-359.
5. Uys CJ, Rose AG. Pathologic findings in long-term cardiac transplants. Arch Pathol Lab I&d 1984;108:112-116. 6. Stamler JS, Vaughan DE, Rudd MA, Mudge GH, Kirschenbaum 5, Young P, Alexander RW, Loscalzo J. Frequency of hypercholesterolemia after heaxt trans. plantation. Am .I Cardiol 1988;62:126&1272. 7. Bilodeau NM, GFitchett DH, Guerraty A, Sniderman AD. Dyslipoproteinemias after heti and heart-lung transplantation: potential relation to accelerated graft arteriosclerosis. .I Heart Transplant 1989;8:454459. 8. Eich D, Thompson JA, KO D, Hastillo A, Lower R, Katz S, Katz M, Hes ML. Hypercholesterolemia in long-term survivors of heti transplantation: early marker of accelerated atherosclerosis. .I Heart Lung Transplant 1991; 10~4549. 9. Lipid Research Cliics Program. The Lipid Research Clinics Coronary Primary Prevention Trial results: I. Reduction in incidence of coronary heart disease. JAMA 1984;251:351-364. 10. Blankenhom D, Nessim S, Johnson R, Sanmaxo M, Azen SC. Beneficial effects of combined colestipol-niacin therapy on coronary atherosclerosis and corenruy venous bypass grafts. JAMA 19X7,257:3233-3240. 11. Frick M, Elo 0, Haapa K, H&en OP, Heinsalmi P, He10 P, Huttonen JK, Kaitaniemi P, Koskinen P, Manninen V, M?ienp% H, MZlki&n M, M&t&i M, Norola S, Pastemack A, Pikkaxainen J, Romo M, Sjiiblom T, NiikilP EA. Helsinki Heart Study: primary-prevention hial with gemfibrozil in middle-aged men with dyslipidemia: safety of treatment, changes in risk factors, and incidence of coronaq heart disease. N Engl J Med 1987;317:1237-1245. 12. Kuo PC, Kirshenbaum JM, Gordon J, Laffel G, Young P, DiSesa VJ, Mudge GH, Vaughan DE. Lovastatin therapy for hypercholesterolemia in cardiac transplant
Cardiac Rehabilitation Adults
recipients. Am J Cardiol 1989,64631~35. 13. Ballantyne CM, Radovancevic B, Farmer JA, Frazier OH, Chandler L, Payton-Ross C, Cocanougher B, Jones PH, Young JB, Gotto AM. Hyperlipidemia after heart transplantation: report of a 6-year experience, with treatment recommendations. J Am Col[ Cardiol 1992;19:1315-1321. 14. Kubo SH, Peters JR, Knutson KR, Hertz MI, Olivari MT, Bolman RM, Hunninghake DB. Factors influencing the development of hypercholesterolemia after heart transplantation. Am J Cardiol 1992;70:52&526. 15. Olivari MY, Kubo SH, Braunlin EA, Bolman RM, Ring WS. Five-year experience with triple-drug immunosuppressive therapy in cardiac transplantation. Circularion 1990;82(suppl IV):IV-27fXV-280. 16. Manual of Laboratoly Operations: Lipid Research Clinics Program: I. Lipid and lipoprotein analysis, Dept. of Health, Education, and Welfare publication (MH) 75-628, National Institutes of Health, 1974. (Revised version issued October, 1982.) 17. Todd PA, Ward A. Gemfibrozil: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in dyslipidaemia. Drugs 1988;36: 314339. 16. Tobert JA. Efficacy and long-term adverse effect pattern of lovastatii. Am J Cardiol 1988;62(suppl):28J-345. 19. Corpier CL, Jones PH, Suki WN, Lederer ED, Quinones MA, Schmidt SW, Young JB. Rhabdomyolysis and renal injury with lows&tin use. JAMA 1988;260: 239-241. 20. Khouy P, Morrison JA, Mellies MJ, Glueck CJ. Weight change since age 18 years in 30. to 55-year-old whites and blacks: associations with lipid values, lipoprotein levels, and blood pressure. JAMA 1983;250:3179-3187.
After Cancer Therapy in Children and Young
Angela M. Sharkey, MD, Andrea B. Carey, ME& Charles T. Heise, CRn, and Gerald Barber, MD pproximately two thirds of 6,000 children diagnosed A with cancer in the United Stateseach year are treated successfully.1With increasing cure rates and longer disease-freesurvival, the long-term outcome of cancer therapy has become important. Both anthracyclines and cardiac irradiation have acute and chronic cardiotoxicity. Previous studies showed that surviving patients of childhood cancer who were treated with these modalities have abnormal exercise tests, echocardiograms and Holter recordings.24 The effects of deconditioning on these tindings is unknown. To separatethe effects of deconditioning secondaryto chronic illness from long-term cardiotoxic effects secondary to anthracyclines, we used exercise testing to study surviving patients of childhood cancer before and after a 1Zweek aerobic conditioning program. We enrolled 12 patients who had undergone successjid treatment of childhood cancer in the study. All patients were postpubertal, had completed chemotherapy for at least I year and were without evidence of residual malignancy. Because a prior, limited, unpublished study in our laboratory showed that children after successful treatment of cancer with minimal anthracyclines and no irradiation have normal exercise parameters (exercise time 8170, maximal oxygen consumption 110% and ventilator-y anaerobic threshold 119% of predicted normal), only those receiving >lOO mglm2 of anthracyclines were enrolled in the present study. Informed consent was obtained from all patients and, where appropriate, their parents. Two patients withdrew from the From the Division of Cardiology, Children’s Hospital of Philadelphia, and the Department of Pediatrics,University of Pennsyhania School of Medicine, Philadelphia, Pennsylvania. Dr. Barber’s current addressis: Room 501, Tisch Hospital, New York University Medical Center, 560 First Avenue, New York, New York 10016.Manuscript received September 16, 1992; revised manuscript received December 4, 1992, and acceptedDecember 5. 1488
THE AMERICANJOURNALOF CARDIOLOGY VOLUME71
program,. 1 had a recurrence of cancer, and the other could not attend the twice weekly sessions.All remaining data apply to the 5 male and 5 female patients who completed the program. Patient diagnoses were acute lymphoblastic leukemia (n = 5), Ewings Tumor (n = 2), and rhabdomyosarcoma, neuroblastoma and Wilms’ Tumor (1 patient each). Mean age at the time of the study was 19 f. 3 years, and at the time of diagnosis 8 IL 4. Cumulative anthracycline dosage rangedfrom 225 to 450 mglm2 (mean 349 Z!I69). Nine of 10 patients received radiation as part of their therapy, with cumulative radiation dosage ranging from 1,800 to 5,500 cGy. Areas of radiation included the central nervous system, spine, cranium and abdomen. Mean hemoglobin at enrollment was 13.5 gldl (range 11.9 to 15.7). At the beginning of the program, all patients completed a questionnaire to assess subjective exercise tolerance, together with individual and family exercise activities including home exercise programs, physical education classes and competitive sp0rts.j All patients then underwent baseline spirometty and percent body fat determination,6,7followed by a maximal cardiopulmonary exercise test using a ramp protoco1.s Oxygen uptake, carbon dioxide production, respiratory quotient, respiratory rate, tidal volume and minute ventilation were measuredon a breath-by-breath basis.Blood pressure was measured at rest, every 3 minutes during exercise, immediately after cessation of exerciseand at 5 minutes of recovery. Cardiac outputs were measuredat rest and every 3 minutes during exercise by an acetylene-helium-carbon monoxide rebreathing technique.9 After completion of the exercise test, the ventilatoty anaerobic threshold was calculated by the V-slope technique.lO Patients then participated in a 12-week, twice-weekly, hospital-based rehabilitation program (Table I) modeled after the program previously shown to be effective JUNE 15,1993
eart Transplant Recipients with
Jeffrey R. Peters, MA, MPH, Spencer 11.Kubo, MD, Maria Teresa Olivari. MD. Kevin I?, Krllts:nl?, nc, alid ihlaid 3. hnnlngtlake, WI mprovements in the diagnosis and therapy of early rejection and infection have resulted in 30% l-year survival for heart transplant recipients.’ However, accelerated coronary vasculopathy is a frequent long-term complication and is the cause of death in up to 20% of patients followed >l year,l” with some degree of vasculopathy noted in all autopsy examinations.4J Hypercholesterolemia,a frequent complication of heart transplantation, appears to be associated with accelerated coronary disease. 3&8 Severalrecent studies have demonstratedthat reducing plasma cholesterol can decreasethe development and the progression of atherosclerosis in both native coronary arteries and bypass grafts.9-11 Based on these factors, there have been several reports on the use of hypolipidemic drugs in heart transplant recipients.12,i3These studies usually involved only a small number of patients and only 1 drug. We therefore retrospectively examinedchangesin lipid values in 71 heart transplant recipients who received drug therapy for hyperlipidemia that was primarily guided by a step-care approach involving gemjibrozil in 2 doses, followed by lovastatin for more resistant cases. From December1983 through August 1991,164 adults (>I8 years of age) underwentheart transplantation at the University of Minnesotaand survived at least I year. From this group, drug therapy was initiated in 71 patients with cholesterollevels that were consistently >240 mgldl, and From the Heart Disease Prevention Clinic and Cardiovascular Division, University of Minnesota Medical School, Minneapolis, Minnesota. Mr. Peters’ address is: Heart Disease Prevention Clinic, Department of Medicine, Box 192, University of Minnesota Hospital and Clinics, University of Minnesota, 401 East River Parkway, Minneapolis, Minnesota 55455. Manuscript received October 13, 1992; revised manuscript received January 4, 1993, and accepted January 5.
thesepatients were entered into this retrospectiveinvestigation. The previous diagnosis of coronary artery disease in 53 (75%) ana! idiopathic cardiomyopathyin 18 (25%) is somewhatdyerent than the international average of50 and 40%, respectively.The time course of lipid changes and the risk factors in$uencing the developmentof hypercholesterolemia in this cohort of patients has been described in an earlier report.14 Tripb-drug immunosuppression15included oral cyclosporine at 2 to 6 mglkglday in 2 divided doses adjusted to maintain a whole blood trough level of 200 nglml for the first 6 months and 100 nglml thereafter. Azathioprine doses were maintained at 2.5 mglkglday with adjustments to maintain a white blood cell count >4000 mm3. Oral prednisone (1 mglkglday) was tapered to 0.3 mglkglday by 3 months and 0.1 mglkglday by 12 months. tIj?er transplant, all patients were instructed on the importance of weight control, exercise, and a low-fat, low-cholesterol diet, but compliance to these lifestyle recommendations was not strictly monitored. Blood pressure, weight and blood chemistries were obtained at most visits. Plasma cholesterol and triglycerides were measured every 3 months using standard Lipid Research Clinics techniques.16Patients receiving lovastatin were monitored jbr creatine kinase elevations after thefirst 2 weeksand then every 3 months. Lipoproteins, low-density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol were not perjormed routinely in the early phases of this study. Thus, paired comparisons of the responseof lipoprotein fractions to transplantation, weight gain or drug therapy are not included. Therapy was initiated with gemfibrozil(600 mglday) in most patients with total plasma cholesterol levels
Started on aemfibrozll
*
Swltched lovastatln
to
n=FJ
-
I200
mg/day
n-37 Remained on 600 mg/day n=7
steps taken by patients iscussion, see text.
drug Or ment in the s&My. For
to
Switched lovastatfn il=5
to
4 Remained on 1200 mg/day n=22 Started
ALL PATIENTS N=7 I
SwItched lovaktatln n=15
on ---+B-
Started on lovastatln n-7
BRIEFREPORTS
X40 mgldl (n = 52, Figure 1). A response was dejned as a reduction in plasma cholesterol to 1240 mgldl or by 210% from post-transplant baseline. If this response was not obtained, the dose of gemfibrozil was increased to 1,200 mglday. For those who did not respond to the higher dose of gemjibrozil, therapy was changed to lovastatin (20 mglday). Somepatients did not follow each station of this step-care approach and bypassed gem@ brozil at the low dose (n = 12), the high dose (n = 8) or both doses (n = 7) before starting lovastatin. All values are reported as mean + SE. Lipid levels before drug treatment were compared to drug treatment levels with paired t tests utilizing the CLINFO system,as were drug responsesbetween steps. A p value co.05 was considered significant. The study included 58 men and 13 women (mean age 50.4 + 1.2 years). After transplantation, total cholesterol increased from 206 + 8 to 289 + 4 mgldl, triglycerides increasedfrom 190 f 18 to 279 f 17 mgl TABLE I Responses
Cholesterol (mg/dl) All patients Responders* Nonresponderst Triglycerides (mg/dl) All patients Responders Nonresponders Weight (kg) All patients Responders Nonresponders
of Patients
to 600
mglday
TABLE II Responses of Patients to 1,200 mg/day of Gemfibrozil
of Gemfibrozil
No.
After Transplant
Gemfibrozil (600 mg/day)
%A
pValue
52 7 45
287 (4) 271 (10) 289 (5)
272 (7) 216 (9) 280 (7)
-5 -20 -3
52 7 45
268 (20) 259 (40) 270 (22)
236 (18) 157 (18) 248 (20)
-12 -39 -8
0.05 <0.05 NS
47 7 40
84 (2) 83 (7)
86 (2) 88 (6) 86 (2)
+3 +5 +2
84 (2)
dl, and weight increasedfrom 74.4 +_1.8 to 81.6 rt 1.8 kg (all p
Cholesterol (mg/dl) All patients* Responderst Nonresponders+ Triglycerides (mg/dl) All patients Responders Nonresponders Weight (kg) All patients Responders Nonresponders *Patients
iPatients who increased gemfibroril Values are expressed as mean i SE.
TABLE Ill
%A
pValue
291 (5) 281 (6) 305 (8)
266 (6) 247 (7) 293 (8)
-9 -12 -4
49 29 20
291(22) 320 (32) 248(24)
204 (15) 201 (21) 207 (22)
-30 -37 -17
41 22 19
81 (4) 80 (6) 82 (6)
85 (2) 84 (3) 87 (3)
increasingdosefrom
Responses of Patients to Lovastatin No.
After Transplant
35 15 8 5 7
299 301 281 317 305
(6) (9) (8) (14) (18)
227 224 210 216 262
35 15 8 5 7
236 235 225 287 212
(17) (27) (35) (46) (36)
225 236 204 230 221
32 15 6 4 7
82 83 86 82 79
(3) (3) (6) (5) (8)
Lovastatin %A
p Value
(7) (8) (8) (13) (25)
-24 -25 -25 -32 -14
(15) (27) 124) (22) (41)
-5 0
NS NS
-9 -20 +4
NS NS NS
(3) (3) (9) (8) (9)
+7 +lO -5 +5 +15
(20 mg/day)
88 90 82 86 91
*Patients stated on 600 mglday of gemfibrozil, titrated to 1,200 mglday, then switched TPatients started on 600 mgldayof gemfibrozil, then switched to lovastatm. ZPatients started on 1,200 mglday of gemfibrozil, then switched to lovastatin. §Patients whose initial therapy was lovastatin. Values are expressed as mean ? SE.
THE AMERICANJOURNALOF CARDIOLOGY VOLUME71
JUNE 15,1993
+5 +4 +6
600 mg (n = 37), plus those whose initial dose was
TPatients remaning on 1,200 mg/day of gemfibrozil. $Patients switching to lovastatin. Values are expressed as mean i SE.
to lovastatin.
Cholesterol (mg/dl) All patients Gemfibrozil 600, 1,200* Gemfibrozil 6007 Gemfibrozil 1,200$ Lovastating Triglycerides (mg/dl) All patients Gemfibrozil600, 1,200 Gemfibrozil 600 Gemfibrozil 1,200 Lovastatin Weight (kg) All patients Gemfibrozil 600, 1,200 Gemfibrozil 600 Gemfibrozil 1,200 Lovastatin
1486
49 29 20
Gemfibrozil (1,200
mg/day)
1,200 mg(n = 12).
*Patients who remained on 600 @day
gemflbrozil. dose or switched
No.
After Transplant
to lovastatin.
who demonstrated an inadequate response to 600 mglday (Table II); 12 patients received an initial dose of 1,200 mglday. For the entire group of 49 patients, total cholesterol decreasedby 25 mgldl (p
tions in cholesterol. Furthermore, gemfibrozil produced large reductions in triglycerides similar in magnitude to other gemtibrozil trials that reported only modest reductions in total cholesterol in mixed hyperlipidemias, but a 50% decreasein ~gty?~r&!es.~~ For those patients who switched to iovastatin, there were generally larger reductions in total cholesterol, averaging 24% for the total group. These responseswere similar to those reported in other studies in heart transplant recipients.r2,13However, in contrast to the response to gemfibrozil, there were usually only small reductions in triglycerides. Tobe@ and Corpier et all9 reported on the high risk of developing myopathy with high-dose lovastatin plus cyclosporine (up to 28% of patients). In this study, lovastatin was discontinued in 1 patient because of a moderate, but asymptomatic, increase in creaturekinase. The low frequency of myopathy with small doses of lovastatin in this study is in agreementwith other investigators.r2,13Thus, low-dose lovastati therapy appears to be well tolerated. Because there is a correlation between weight gain and lipid levels,2o it could be anticipated that there would be greater reductions in total cholesterol and triglycerides if weight had at least stabilized during postoperative follow-up. However, weight gain was observed in both respondersand nonrespondersand therefore was not correlated with cholesterol or triglyceride changes. Several additional factors could have affected the responsesto lipid-lowering therapy. Although instructions regarding low cholesterol, low saturated fat diets were provided for each patient, it is likely that variable compliance with these recommendations could have affected drug responses. There was no systematic taper of prednisone or cyclosporine in these patients, but it is possible that some patients were more sensitive to the hyperlipidemic effects of these drugs. Because this was a short-term study, the effects of treatment on the development of allograft vasculopathy and whether there are any important differencesbetween the drugs are not yet known. The examination of subgroup responsesrather than focusing on mean changes, highlights the heterogeneity of the therapeutic responses. From these data, we believe that a small percentage of patients will have a significant reduction in cholesterol with gemfibrozil alone. The cholesterol decreases with lovastatin will generally be larger, but the reduction in triglycerides will be less. Practitioners should be aware of the differencesin efficacy between these agents when considering hypolipidemic therapy in transplant patients, 1. k’ietl JM, Kaye MI’. The re@stq of the International Sociely for Heart and Lung Transplantation: eighth official report - 1991. JHeurt Lang Trarzsplant 1991; 10:49149x. 2. Uretsky BF, Murali S, Reddy PS, Rabin B, Lee A, Griffith BP, Hard&y RI,, Trento A, Bahnson m. Development of coronary artery discax in cardiac trans. plant patients receiving immunosuppressive therapy with cyclosporine aId pro&isane. Circulation 1987;76:827-834. 3. Babii M, Banner N, Thompson GR, Kbaghani A, Mitchell A, Yacoub M. Rdationship of inmmnosuppression and scmm lipids to the development of coronay arterial disease in the transplanted heart. lnt ./ Car&Z 1991;32:51-56. 4. Johnson DE, Gao Sz, Scbuxdcr JS, DeCampi WM, Billingham ME. The spectrum of coronary arlery pathology in human cardiac allografts. J Heart Transplant 1989;8:349-359.
5. Uys CJ, Rose AG. Pathologic findings in long-term cardiac transplants. Arch Pathol Lab I&d 1984;108:112-116. 6. Stamler JS, Vaughan DE, Rudd MA, Mudge GH, Kirschenbaum 5, Young P, Alexander RW, Loscalzo J. Frequency of hypercholesterolemia after heaxt trans. plantation. Am .I Cardiol 1988;62:126&1272. 7. Bilodeau NM, GFitchett DH, Guerraty A, Sniderman AD. Dyslipoproteinemias after heti and heart-lung transplantation: potential relation to accelerated graft arteriosclerosis. .I Heart Transplant 1989;8:454459. 8. Eich D, Thompson JA, KO D, Hastillo A, Lower R, Katz S, Katz M, Hes ML. Hypercholesterolemia in long-term survivors of heti transplantation: early marker of accelerated atherosclerosis. .I Heart Lung Transplant 1991; 10~4549. 9. Lipid Research Cliics Program. The Lipid Research Clinics Coronary Primary Prevention Trial results: I. Reduction in incidence of coronary heart disease. JAMA 1984;251:351-364. 10. Blankenhom D, Nessim S, Johnson R, Sanmaxo M, Azen SC. Beneficial effects of combined colestipol-niacin therapy on coronary atherosclerosis and corenruy venous bypass grafts. JAMA 19X7,257:3233-3240. 11. Frick M, Elo 0, Haapa K, H&en OP, Heinsalmi P, He10 P, Huttonen JK, Kaitaniemi P, Koskinen P, Manninen V, M?ienp% H, MZlki&n M, M&t&i M, Norola S, Pastemack A, Pikkaxainen J, Romo M, Sjiiblom T, NiikilP EA. Helsinki Heart Study: primary-prevention hial with gemfibrozil in middle-aged men with dyslipidemia: safety of treatment, changes in risk factors, and incidence of coronaq heart disease. N Engl J Med 1987;317:1237-1245. 12. Kuo PC, Kirshenbaum JM, Gordon J, Laffel G, Young P, DiSesa VJ, Mudge GH, Vaughan DE. Lovastatin therapy for hypercholesterolemia in cardiac transplant
Cardiac Rehabilitation Adults
recipients. Am J Cardiol 1989,64631~35. 13. Ballantyne CM, Radovancevic B, Farmer JA, Frazier OH, Chandler L, Payton-Ross C, Cocanougher B, Jones PH, Young JB, Gotto AM. Hyperlipidemia after heart transplantation: report of a 6-year experience, with treatment recommendations. J Am Col[ Cardiol 1992;19:1315-1321. 14. Kubo SH, Peters JR, Knutson KR, Hertz MI, Olivari MT, Bolman RM, Hunninghake DB. Factors influencing the development of hypercholesterolemia after heart transplantation. Am J Cardiol 1992;70:52&526. 15. Olivari MY, Kubo SH, Braunlin EA, Bolman RM, Ring WS. Five-year experience with triple-drug immunosuppressive therapy in cardiac transplantation. Circularion 1990;82(suppl IV):IV-27fXV-280. 16. Manual of Laboratoly Operations: Lipid Research Clinics Program: I. Lipid and lipoprotein analysis, Dept. of Health, Education, and Welfare publication (MH) 75-628, National Institutes of Health, 1974. (Revised version issued October, 1982.) 17. Todd PA, Ward A. Gemfibrozil: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in dyslipidaemia. Drugs 1988;36: 314339. 16. Tobert JA. Efficacy and long-term adverse effect pattern of lovastatii. Am J Cardiol 1988;62(suppl):28J-345. 19. Corpier CL, Jones PH, Suki WN, Lederer ED, Quinones MA, Schmidt SW, Young JB. Rhabdomyolysis and renal injury with lows&tin use. JAMA 1988;260: 239-241. 20. Khouy P, Morrison JA, Mellies MJ, Glueck CJ. Weight change since age 18 years in 30. to 55-year-old whites and blacks: associations with lipid values, lipoprotein levels, and blood pressure. JAMA 1983;250:3179-3187.
After Cancer Therapy in Children and Young
Angela M. Sharkey, MD, Andrea B. Carey, ME& Charles T. Heise, CRn, and Gerald Barber, MD pproximately two thirds of 6,000 children diagnosed A with cancer in the United Stateseach year are treated successfully.1With increasing cure rates and longer disease-freesurvival, the long-term outcome of cancer therapy has become important. Both anthracyclines and cardiac irradiation have acute and chronic cardiotoxicity. Previous studies showed that surviving patients of childhood cancer who were treated with these modalities have abnormal exercise tests, echocardiograms and Holter recordings.24 The effects of deconditioning on these tindings is unknown. To separatethe effects of deconditioning secondaryto chronic illness from long-term cardiotoxic effects secondary to anthracyclines, we used exercise testing to study surviving patients of childhood cancer before and after a 1Zweek aerobic conditioning program. We enrolled 12 patients who had undergone successjid treatment of childhood cancer in the study. All patients were postpubertal, had completed chemotherapy for at least I year and were without evidence of residual malignancy. Because a prior, limited, unpublished study in our laboratory showed that children after successful treatment of cancer with minimal anthracyclines and no irradiation have normal exercise parameters (exercise time 8170, maximal oxygen consumption 110% and ventilator-y anaerobic threshold 119% of predicted normal), only those receiving >lOO mglm2 of anthracyclines were enrolled in the present study. Informed consent was obtained from all patients and, where appropriate, their parents. Two patients withdrew from the From the Division of Cardiology, Children’s Hospital of Philadelphia, and the Department of Pediatrics,University of Pennsyhania School of Medicine, Philadelphia, Pennsylvania. Dr. Barber’s current addressis: Room 501, Tisch Hospital, New York University Medical Center, 560 First Avenue, New York, New York 10016.Manuscript received September 16, 1992; revised manuscript received December 4, 1992, and acceptedDecember 5. 1488
THE AMERICANJOURNALOF CARDIOLOGY VOLUME71
program,. 1 had a recurrence of cancer, and the other could not attend the twice weekly sessions.All remaining data apply to the 5 male and 5 female patients who completed the program. Patient diagnoses were acute lymphoblastic leukemia (n = 5), Ewings Tumor (n = 2), and rhabdomyosarcoma, neuroblastoma and Wilms’ Tumor (1 patient each). Mean age at the time of the study was 19 f. 3 years, and at the time of diagnosis 8 IL 4. Cumulative anthracycline dosage rangedfrom 225 to 450 mglm2 (mean 349 Z!I69). Nine of 10 patients received radiation as part of their therapy, with cumulative radiation dosage ranging from 1,800 to 5,500 cGy. Areas of radiation included the central nervous system, spine, cranium and abdomen. Mean hemoglobin at enrollment was 13.5 gldl (range 11.9 to 15.7). At the beginning of the program, all patients completed a questionnaire to assess subjective exercise tolerance, together with individual and family exercise activities including home exercise programs, physical education classes and competitive sp0rts.j All patients then underwent baseline spirometty and percent body fat determination,6,7followed by a maximal cardiopulmonary exercise test using a ramp protoco1.s Oxygen uptake, carbon dioxide production, respiratory quotient, respiratory rate, tidal volume and minute ventilation were measuredon a breath-by-breath basis.Blood pressure was measured at rest, every 3 minutes during exercise, immediately after cessation of exerciseand at 5 minutes of recovery. Cardiac outputs were measuredat rest and every 3 minutes during exercise by an acetylene-helium-carbon monoxide rebreathing technique.9 After completion of the exercise test, the ventilatoty anaerobic threshold was calculated by the V-slope technique.lO Patients then participated in a 12-week, twice-weekly, hospital-based rehabilitation program (Table I) modeled after the program previously shown to be effective JUNE 15,1993