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Pravastatin therapy is associated with reduction in coronary allograft vasculopathy in pediatric heart transplantation
Pravastatin Therapy is Associated With Reduction in Coronary Allograft Vasculopathy in Pediatric Heart Transplantation William T. Mahle, MD,a Robert N. Vincent, MD,a Alexandria M. Berg, RN,b and Kirk R. Kanter, MDb Background: Hydroxymethylglutaryl CoA reductase inhibitors (statins) have been demonstrated to reduce the risk of developing coronary allograft vasculopathy (CAV) following heart transplantation in adults and are used routinely in many centers. CAV and lipid abnormalities have been reported to be less prevalent in pediatric heart transplant recipients. It is not known whether statins reduce the risk of CAV in this population Methods: A retrospective review was performed to analyze the risk factors for developing CAV following pediatric heart transplantation with particular attention to the impact of pravastatin therapy. The study population was comprised of 129 pediatric patients who underwent 142 heart transplants at our institution from 1988 to 2003. The outcome variable was freedom from CAV, CAV being determined by coronary angiography or autopsy. Results: CAV was identified in 25 recipients at a median of 3.7 years after transplantation. There were 331 patient-years of pravastatin therapy. Pravastatin therapy resulted in a reduction in total cholesterol levels, 162 ⫾ 29 to 137 ⫾ 20 mg/dl, p ⫽ 0.01. In multivariate analysis the use of pravastatin was associated with a lower incidence of CAV (p ⫽ 0.03), whereas an increased frequency of late rejection (p ⫽ 0.003) and earlier year of transplantation (p ⫽ 0.04) were associated with increased risk of CAV. Conclusions: The routine use of pravastatin was associated with a lower risk following pediatric heart transplantation. Further studies into the relationship between lipid abnormalities, inflammation and rejection, and the development of CAV in children are warranted. J Heart Lung Transplant 2005;24: 63– 6. Copyright © 2005 by the International Society for Heart and Lung Transplantation.
Cardiac allograft vasculopathy (CAV) is one of the major causes of mortality late after heart transplantation.1 Statin therapy such as 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors have been reported to reduce the incidence of CAV in adult heart transplant recipients.2,3 The protective effects of statins have been attributed to improved lipid profiles, immunomodulation, and anti-inflammatory effects.2–5 The incidence of CAV in pediatric heart transplant recipients has varied from 6% to 30% at 5 years, but is generally thought to be less prevalent than in adult heart transplant recipients.6 –9 In addition, significant lipid abnormalities are less prevalent in pediatric heart
From the aChildren’s Healthcare of Atlanta and Department of Pediatrics, Division of Cardiology, bDepartment of Surgery, Division of Cardiothoracic Surgery, Emory University School of Medicine, Atlanta, Georgia. Submitted August 27, 2003; revised October 3, 2003; accepted October 23, 2003. Reprint requests: William T. Mahle, MD, Children’s Healthcare of Atlanta, Emory University School of Medicine, 1405 Clifton Road, NE, Atlanta, GA 30322-1062. Telephone: 404-315-2672. Fax: 404-3256021. E-mail: [email protected] Copyright © 2005 by the International Society for Heart and Lung Transplantation. 1053-2498/05/$–see front matter. doi:10.1016/ j.healun.2003.10.013
transplant recipients.7 It is unclear, therefore, whether statin therapy should be used routinely in the management following pediatric heart transplantation. In the present study we sought to determine whether statin therapy reduces the risk of developing CAV. MATERIAL AND METHODS Between July 1988 and December 2002, 129 patients underwent 142 heart transplantations at Children Healthcare of Atlanta at Egleston. The transplantations were orthotopic in 141 and heterotopic in 1 patient. All patients were managed with triple immunosuppression following heart transplantation. Immunosuppression consisted of: calcineurin inhibitors, cyclosporin or tacrolimus; antimetabolites, azathioprine or mycophenolate mofetil; and corticosteroids. Steroid dosage was tapered and discontinued whenever possible according to the results of regularly scheduled surveillance endomyocardial biopsies. Episodes of focal moderate or moderate cardiac rejection (grades 2 and 3, respectively, of the classification system of the International Society for Heart and Lung Transplantation [ISHLT]) were diagnosed on the basis of analysis of endomyocardial biopsy specimens by pathologist and transplant physician. Diagnosis of CAV was made by coronary angiography, which was performed on an annual basis or if 63
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Table 1. Variables Analyzed for Association with CAV Variable Gender Age at transplantation Congenital heart disease Previous sternotomy UNOS status Ventricular assist device Mechanical ventilation Donor ischemic time Pre-transplant panel reactive antibody titer CMV mismatch Pravastatin therapy Cylosporine therapy* Azathioprine therapy† ⴱ
Instead of tacrolimus; †instead of mycophenolate mofetil. CAV, coronary allograft vasculopathy; CMV, cytomegalovirus; UNOS, United Network of Organ Sharing.
clinically indicated. Angiograms were considered to be positive for CAV if there was stenosis (luminal narrowing) of 50% or more or substantial distal pruning of the coronary arteries. In addition, autopsy specimens were analyzed for CAV. Based on literature from adult heart transplant patients, we instituted a policy of routine therapy with pravastatin beginning in 1998. Pravastatin was administered at a dose of 0.2 mg/kg per day. Lipid profile and hepatic function was monitored annually. Statistical Analysis Data are expressed as mean ⫾ standard deviation (SD) or median and range, where appropriate. Actuarial survival curves assessing time to event of were constructed using the method of Kaplan-Meier. We analyzed time to CAV using proportional hazards regression. Variables analyzed for association with CAV are shown in Table 1. Late rejection episodes were defined as the number of rejection episodes/year that occurred more than 1 year after transplantation. Stepwise regression was performed with variables with a p value ⬍ 0.15 remaining in the model. As patients transplanted before 1998 did not routinely receive pravastatin until 1998, pravastatin therapy was treated as a time-dependent covariate according to the methods described by Crowley and Hu.10 Significance was determined at p ⬍ 0.05. All p values are two-sided and confidence intervals are 95%. Analysis was performed with STATA 6.0 (College Station, TX). RESULTS During the study period, 129 children underwent 142 heart transplants at a median age of 7.3 years, range: 22 days to 18.8 years. One-hundred twenty-six patients survived ⬎6 months. The mean follow-up period for survivors was 6.1 ⫾ 3.7 years. CAV was identified in 25 heart transplant recipients (17.6%). CAV was diagnosed by angiography in 19 patients
The Journal of Heart and Lung Transplantation January 2005
and by autopsy in 6 patients. Freedom from CAV at 3, 5, and 10 years after transplant was 92%, 87%, and 71%, respectively. The actuarial survival for the entire cohort was 82% at 1 year, 72% at 3 years, and 61% at 5 years. The cause of death in descending order was sepsis and multi-system organ failure (n ⫽ 12), CAV (n ⫽ 8), acute rejection (n ⫽ 6), early graft failure (n ⫽ 5), non-specific graft failure (n ⫽ 5), post-transplant lymphoproliferative disease (n ⫽ 4), sudden death (n ⫽ 3), and other (n ⫽ 10). Pravastatin therapy was initiated in 90 patients. In 57 patients it was started in the immediate post-transplant period. There were 33 patients who began pravastatin therapy 6 months or more after transplantation. For the patients not begun on pravastatin until at least 6 months after transplantation, the median time elapsed between the time of transplantation and commencement of pravastatin was 3.2 years, range: 0.74 to 9.4 years. Dosing ranged from 0.1 to 0.3 mg/kg per day. There were 3 patients who discontinued therapy due to side effects: 2 patients developed leg pain, 1 patient developed headaches. A cohort of patients (n ⫽ 22) who were not placed on statin therapy until at least 2 years after transplantation who were on chronic stable immunosuppression were also examined in order to determine the impact of statin therapy on the lipid profile. Lipid panels just before starting statin therapy and 1 year later are illustrated in Figure 1. Before initiation of statin therapy 6 of 22 patients (22%) had total cholesterol levels ⱖ 180 mg/dl. Pravastatin resulted in small but significant reduction in total cholesterol 162 ⫾ 29 to 137 ⫾ 20 mg/dl, p ⫽ 0.01. No significant changes in trigylcerides were noted. In univariate analysis there was a trend toward a lower incidence of CAV and patients treated with pravastatin (Figure 2). When other patient and procedure-related factors were considered in multivariate logistic regression, pravastatin therapy was associated with a statistically significant reduction of CAV (Table 2). Additional risk factors for the development of CAV were late rejection frequency and earlier year of transplantation. DISCUSSION The reported prevalence of CAV following pediatric heart transplantation has varied from 6% to 30%.6 –9 In the present study we found the prevalence of CAV to be 13% at 5 years after transplantation. The present study demonstrated that the routine use of pravastatin following heart transplantation in children reduces total cholesterol levels and is associated with a reduced risk of developing CAV. There are no prior studies that address the potential protective effect of statin on the development of CAV in children. In general perturbations of lipid profile have been reported to be less prevalent in pediatric heart transplant recipients when compared to adults. Mulla and colleagues7 reported serum cholesterol and triglyceride levels within normal range for a cohort of children
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Figure 1. Change in total cholesterol and triglyceride levels before and 1 year after pravastatin therapy in 22 patients.
who had undergone heart transplantation and found no association between cholesterol levels and CAV. However, the median age at follow-up was relatively young, 5 years of age, and most patients had undergone transplantation as infants. Several other investigators have reported that cholesterol and triglyceride levels are significantly elevated in school-age and adolescent heart transplant recipients.11,12 In the present study we found perturbations in lipid profiles, although generally mild, to be common. Statin therapy results in a more favorable lipid profile in children following transplantation. Chin et al12 reported that significant declines in total cholesterol (20%), triglyceride (18%), and LDL (26%) were observed after starting atorvastatin therapy. There were no significant changes in HDL or VLDL compared with baseline. There were also no differences in alanine transaminase pre- versus post-atorvastatin therapy. Penson and colleagues11 found that pravastatin significantly decreased total cholesterol and LDL cholesterol. Interestingly, these authors found that pravastatin had a more significant effect in patients managed with cyclosporine compared to tacrolimus due at least in part to the greater degree of lipid abnormalities associated with
Table 2. Risk Factors for Coronary Allograft Vasculopathy Patient and procedure-related variables Pravastatin therapy Earlier year of transplant Late rejection Panel reactive antibody ⬎10% CI, confidence interval.
Hazard ratio 0.29 2.03 2.27 1.02
95% CI 0.09–0.96 1.03–4.16 1.31–3.92 0.97–1.03
p Value 0.03 0.04 0.003 0.13
cyclosporine. At our institution, cyclosporine is the preferred calcineurin inhibitor. Even though lipid levels may be only mildly elevated in most pediatric heart transplant recipients, it is not surprising that statin therapy appears to protective with regards to CAV. See and colleagues13 have described that atorvastatin administered to adult patients with normal or mild hypercholesterolemia in the initial year after transplant prevented the development and progression of coronary artery lesions and endothelial dysfunction with only mild long-term decreases in cholesterol levels. Several non-lipid related mechanisms have been proposed. These include well-demonstrated immunomodulatory effects. Kobashigawa and colleagues2 demonstrated that the cytoxicity of natural killer cells was lower in adult transplant patients treated with pravastatin. Additional putative mechanisms by which statins modulate the immune system include regulating inducible class II major histocompatibility complex expression on macrophages and endothelial cells.14 In the present study we also found that CAV was associated with late rejection episodes, whereas early rejection (within the first year post-transplant) was not. Mulla and colleagues7 reported similar findings. These findings support the hypothesis that the etiology of CAV is multifactorial and that immunosuppressive interventions are likely to influence the development of CAV. A number of other factors have been suggested as risk factors for the development of CAV in pediatric heart transplant recipient, these include: older age, donor:recipient race mismatch, immunosuppressant regimen, and non-compliance.6 – 8 In our study population, which included 39 (30%) subjects transplanted in infancy (⬍1 year of age), age of recipient was not associated with development of CAV. The failure to
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Figure 2. Kaplan-Meier plot of freedom from coronary allograft vasculopathy (CAV) stratified by use of pravastatin therapy (univariate analysis).
detect such an association may be related to a relatively small study population. Ongoing studies in adult transplant recipients are examining in greater detail the impact of statin dosage and differences in immunomodulatory and lipid-lowering effects of various statins. In the present study we used pravastatin at doses of 0.2 mg/kg per day. These doses are slightly less than those sometimes prescribed to adults (40 mg) or approximately 0.5 to 0.6 mg/kg per day.2 In addition, some investigators have suggested that statins other than pravastatin may be more beneficial in the heart transplant population. Magnani and colleagues15 reported that compared to pravastatin atorvastatin reduced total cholesterol, LDL cholesterol, and triglycerides, at lower doses and with comparable tolerability and safety. Prospective studies may be needed to determine whether there are significant benefits of one particular statin in pediatric heart transplantation. The present study has several recognized limitations. The detection of CAV was limited to angiographic assessment and post-mortem examinations. As such less severe degrees of CAV as can be detected by intravascular ultrasound were not reported. In addition, the administration of pravastatin was not randomized. In summary pravastatin therapy was associated with a significant reduction in CAV in pediatric heart transplant recipients. We believe that statin therapy should be administered routinely in following heart transplantation in children. Further studies are warranted to better understand the coronary-protective effects in children, especially those with normal lipid profiles. REFERENCES 1. Fraund S, Pethig K, Franke U, et al. Ten year survival after heart transplantation: palliative procedure or successful longterm treatment? Heart 1999;82:47–51.
The Journal of Heart and Lung Transplantation January 2005
2. Kobashigawa JA, Katznelson S, Laks H, et al. Effect of pravastatin on outcomes after cardiac transplantation. N Engl J Med 1995;333:621–7. 3. Wenke K, Meiser B, Thiery J, et al. Simvastastin reduces graft vessel disease and mortality after heart transplantation: a four-year randomized trial. Circulation 1997;96: 1398 –402. 4. Shishehbor MH, Brennan ML, Aviles RJ, et al. Statins promote potent systemic antioxidant effects through specific inflammatory pathways. Circulation 2003;108: 426 –31. 5. Katznelson S. Immunosuppressive and antiproliferative effects of HMG-CoA reductase inhibitors. Transplant Proc 1991;31(3B Suppl):22S–24S. 6. Pahl E, Naftel DC, Kuhn MA, Shaddy RE, Morrow R, Kirklin JJ. The incidence of and impact of transplant coronary artery disease in pediatric recipients: a 9 year multi-institutional study (abstr). Circulation 2002;10:II396. 7. Mulla NF, Johnston JK, Vander Dussen L, et al. Late rejection is a predictor of transplant coronary artery disease in children. J Am Coll Cardiol 2001;37:243–50. 8. Addonizio LJ, Hsu DT, Douglas JF, et al. Decreasing incidence of coronary artery disease in pediatric heart transplant recipients using increased immunosuppression. Circulation 1993;88(5 Pt 2):II224 –9. 9. Hirsch R, Balzer DT, Dent CL, Huddleston CB, Mendeloff EN, Canter CE. Outcome after diagnosis of moderatesevere transplant coronary artery disease (TCAD) in pediatric heart transplant recipients. J Heart Lung Transplant 2001;20:261–2. 10. Crowley J, Hu M. Covariance analysis of heart transplant survival data. J Am Stat Assoc 1977;72:27–36. 11. Penson MG, Fricker FJ, Thompson JR, et al. Safety and efficacy of pravastatin therapy for the prevention of hyperlipidemia in pediatric and adolescent cardiac transplant recipients. J Heart Lung Transplant 200;20: 611– 8. 12. Chin C, Gamberg P, Miller J, Luikart H, Bernstein D. Efficacy and safety of atorvastatin after pediatric heart transplantation. J Heart Lung Transplant 2002;21:1213–7. 13. See VY, Jr, DeNofrio D, Goldberg L, et al. Effect of atorvastatin on postcardiac transplant increase in lowdensity lipoprotein cholesterol reduces development of intimal hyperplasia and progression of endothelial dysfunction. Am J Cardiol 2003;92:11–5. 14. Sadeghi MM, Tiglio A, Sadigh K, et al. Inhibition of interferon-gamma-mediated microvascular endothelial cell major histocompatibility complex class II gene activation by HMG-CoA reductase inhibitors. Transplantation 2001;71:1262–8. 15. Magnani G, Carinci V, Magelli C, Potena L, Reggiani LB, Branzi A. Role of statins in the management of dyslipidemia after cardiac transplant: randomized controlled trial comparing the efficacy and the safety of atorvastatin with pravastatin. J Heart Lung Transplant 2000;19: 710 –5.
Cardiac allograft vasculopathy (CAV) is one of the major causes of mortality late after heart transplantation.1 Statin therapy such as 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors have been reported to reduce the incidence of CAV in adult heart transplant recipients.2,3 The protective effects of statins have been attributed to improved lipid profiles, immunomodulation, and anti-inflammatory effects.2–5 The incidence of CAV in pediatric heart transplant recipients has varied from 6% to 30% at 5 years, but is generally thought to be less prevalent than in adult heart transplant recipients.6 –9 In addition, significant lipid abnormalities are less prevalent in pediatric heart
From the aChildren’s Healthcare of Atlanta and Department of Pediatrics, Division of Cardiology, bDepartment of Surgery, Division of Cardiothoracic Surgery, Emory University School of Medicine, Atlanta, Georgia. Submitted August 27, 2003; revised October 3, 2003; accepted October 23, 2003. Reprint requests: William T. Mahle, MD, Children’s Healthcare of Atlanta, Emory University School of Medicine, 1405 Clifton Road, NE, Atlanta, GA 30322-1062. Telephone: 404-315-2672. Fax: 404-3256021. E-mail: [email protected] Copyright © 2005 by the International Society for Heart and Lung Transplantation. 1053-2498/05/$–see front matter. doi:10.1016/ j.healun.2003.10.013
transplant recipients.7 It is unclear, therefore, whether statin therapy should be used routinely in the management following pediatric heart transplantation. In the present study we sought to determine whether statin therapy reduces the risk of developing CAV. MATERIAL AND METHODS Between July 1988 and December 2002, 129 patients underwent 142 heart transplantations at Children Healthcare of Atlanta at Egleston. The transplantations were orthotopic in 141 and heterotopic in 1 patient. All patients were managed with triple immunosuppression following heart transplantation. Immunosuppression consisted of: calcineurin inhibitors, cyclosporin or tacrolimus; antimetabolites, azathioprine or mycophenolate mofetil; and corticosteroids. Steroid dosage was tapered and discontinued whenever possible according to the results of regularly scheduled surveillance endomyocardial biopsies. Episodes of focal moderate or moderate cardiac rejection (grades 2 and 3, respectively, of the classification system of the International Society for Heart and Lung Transplantation [ISHLT]) were diagnosed on the basis of analysis of endomyocardial biopsy specimens by pathologist and transplant physician. Diagnosis of CAV was made by coronary angiography, which was performed on an annual basis or if 63
64
Mahle et al.
Table 1. Variables Analyzed for Association with CAV Variable Gender Age at transplantation Congenital heart disease Previous sternotomy UNOS status Ventricular assist device Mechanical ventilation Donor ischemic time Pre-transplant panel reactive antibody titer CMV mismatch Pravastatin therapy Cylosporine therapy* Azathioprine therapy† ⴱ
Instead of tacrolimus; †instead of mycophenolate mofetil. CAV, coronary allograft vasculopathy; CMV, cytomegalovirus; UNOS, United Network of Organ Sharing.
clinically indicated. Angiograms were considered to be positive for CAV if there was stenosis (luminal narrowing) of 50% or more or substantial distal pruning of the coronary arteries. In addition, autopsy specimens were analyzed for CAV. Based on literature from adult heart transplant patients, we instituted a policy of routine therapy with pravastatin beginning in 1998. Pravastatin was administered at a dose of 0.2 mg/kg per day. Lipid profile and hepatic function was monitored annually. Statistical Analysis Data are expressed as mean ⫾ standard deviation (SD) or median and range, where appropriate. Actuarial survival curves assessing time to event of were constructed using the method of Kaplan-Meier. We analyzed time to CAV using proportional hazards regression. Variables analyzed for association with CAV are shown in Table 1. Late rejection episodes were defined as the number of rejection episodes/year that occurred more than 1 year after transplantation. Stepwise regression was performed with variables with a p value ⬍ 0.15 remaining in the model. As patients transplanted before 1998 did not routinely receive pravastatin until 1998, pravastatin therapy was treated as a time-dependent covariate according to the methods described by Crowley and Hu.10 Significance was determined at p ⬍ 0.05. All p values are two-sided and confidence intervals are 95%. Analysis was performed with STATA 6.0 (College Station, TX). RESULTS During the study period, 129 children underwent 142 heart transplants at a median age of 7.3 years, range: 22 days to 18.8 years. One-hundred twenty-six patients survived ⬎6 months. The mean follow-up period for survivors was 6.1 ⫾ 3.7 years. CAV was identified in 25 heart transplant recipients (17.6%). CAV was diagnosed by angiography in 19 patients
The Journal of Heart and Lung Transplantation January 2005
and by autopsy in 6 patients. Freedom from CAV at 3, 5, and 10 years after transplant was 92%, 87%, and 71%, respectively. The actuarial survival for the entire cohort was 82% at 1 year, 72% at 3 years, and 61% at 5 years. The cause of death in descending order was sepsis and multi-system organ failure (n ⫽ 12), CAV (n ⫽ 8), acute rejection (n ⫽ 6), early graft failure (n ⫽ 5), non-specific graft failure (n ⫽ 5), post-transplant lymphoproliferative disease (n ⫽ 4), sudden death (n ⫽ 3), and other (n ⫽ 10). Pravastatin therapy was initiated in 90 patients. In 57 patients it was started in the immediate post-transplant period. There were 33 patients who began pravastatin therapy 6 months or more after transplantation. For the patients not begun on pravastatin until at least 6 months after transplantation, the median time elapsed between the time of transplantation and commencement of pravastatin was 3.2 years, range: 0.74 to 9.4 years. Dosing ranged from 0.1 to 0.3 mg/kg per day. There were 3 patients who discontinued therapy due to side effects: 2 patients developed leg pain, 1 patient developed headaches. A cohort of patients (n ⫽ 22) who were not placed on statin therapy until at least 2 years after transplantation who were on chronic stable immunosuppression were also examined in order to determine the impact of statin therapy on the lipid profile. Lipid panels just before starting statin therapy and 1 year later are illustrated in Figure 1. Before initiation of statin therapy 6 of 22 patients (22%) had total cholesterol levels ⱖ 180 mg/dl. Pravastatin resulted in small but significant reduction in total cholesterol 162 ⫾ 29 to 137 ⫾ 20 mg/dl, p ⫽ 0.01. No significant changes in trigylcerides were noted. In univariate analysis there was a trend toward a lower incidence of CAV and patients treated with pravastatin (Figure 2). When other patient and procedure-related factors were considered in multivariate logistic regression, pravastatin therapy was associated with a statistically significant reduction of CAV (Table 2). Additional risk factors for the development of CAV were late rejection frequency and earlier year of transplantation. DISCUSSION The reported prevalence of CAV following pediatric heart transplantation has varied from 6% to 30%.6 –9 In the present study we found the prevalence of CAV to be 13% at 5 years after transplantation. The present study demonstrated that the routine use of pravastatin following heart transplantation in children reduces total cholesterol levels and is associated with a reduced risk of developing CAV. There are no prior studies that address the potential protective effect of statin on the development of CAV in children. In general perturbations of lipid profile have been reported to be less prevalent in pediatric heart transplant recipients when compared to adults. Mulla and colleagues7 reported serum cholesterol and triglyceride levels within normal range for a cohort of children
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Figure 1. Change in total cholesterol and triglyceride levels before and 1 year after pravastatin therapy in 22 patients.
who had undergone heart transplantation and found no association between cholesterol levels and CAV. However, the median age at follow-up was relatively young, 5 years of age, and most patients had undergone transplantation as infants. Several other investigators have reported that cholesterol and triglyceride levels are significantly elevated in school-age and adolescent heart transplant recipients.11,12 In the present study we found perturbations in lipid profiles, although generally mild, to be common. Statin therapy results in a more favorable lipid profile in children following transplantation. Chin et al12 reported that significant declines in total cholesterol (20%), triglyceride (18%), and LDL (26%) were observed after starting atorvastatin therapy. There were no significant changes in HDL or VLDL compared with baseline. There were also no differences in alanine transaminase pre- versus post-atorvastatin therapy. Penson and colleagues11 found that pravastatin significantly decreased total cholesterol and LDL cholesterol. Interestingly, these authors found that pravastatin had a more significant effect in patients managed with cyclosporine compared to tacrolimus due at least in part to the greater degree of lipid abnormalities associated with
Table 2. Risk Factors for Coronary Allograft Vasculopathy Patient and procedure-related variables Pravastatin therapy Earlier year of transplant Late rejection Panel reactive antibody ⬎10% CI, confidence interval.
Hazard ratio 0.29 2.03 2.27 1.02
95% CI 0.09–0.96 1.03–4.16 1.31–3.92 0.97–1.03
p Value 0.03 0.04 0.003 0.13
cyclosporine. At our institution, cyclosporine is the preferred calcineurin inhibitor. Even though lipid levels may be only mildly elevated in most pediatric heart transplant recipients, it is not surprising that statin therapy appears to protective with regards to CAV. See and colleagues13 have described that atorvastatin administered to adult patients with normal or mild hypercholesterolemia in the initial year after transplant prevented the development and progression of coronary artery lesions and endothelial dysfunction with only mild long-term decreases in cholesterol levels. Several non-lipid related mechanisms have been proposed. These include well-demonstrated immunomodulatory effects. Kobashigawa and colleagues2 demonstrated that the cytoxicity of natural killer cells was lower in adult transplant patients treated with pravastatin. Additional putative mechanisms by which statins modulate the immune system include regulating inducible class II major histocompatibility complex expression on macrophages and endothelial cells.14 In the present study we also found that CAV was associated with late rejection episodes, whereas early rejection (within the first year post-transplant) was not. Mulla and colleagues7 reported similar findings. These findings support the hypothesis that the etiology of CAV is multifactorial and that immunosuppressive interventions are likely to influence the development of CAV. A number of other factors have been suggested as risk factors for the development of CAV in pediatric heart transplant recipient, these include: older age, donor:recipient race mismatch, immunosuppressant regimen, and non-compliance.6 – 8 In our study population, which included 39 (30%) subjects transplanted in infancy (⬍1 year of age), age of recipient was not associated with development of CAV. The failure to
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Mahle et al.
Figure 2. Kaplan-Meier plot of freedom from coronary allograft vasculopathy (CAV) stratified by use of pravastatin therapy (univariate analysis).
detect such an association may be related to a relatively small study population. Ongoing studies in adult transplant recipients are examining in greater detail the impact of statin dosage and differences in immunomodulatory and lipid-lowering effects of various statins. In the present study we used pravastatin at doses of 0.2 mg/kg per day. These doses are slightly less than those sometimes prescribed to adults (40 mg) or approximately 0.5 to 0.6 mg/kg per day.2 In addition, some investigators have suggested that statins other than pravastatin may be more beneficial in the heart transplant population. Magnani and colleagues15 reported that compared to pravastatin atorvastatin reduced total cholesterol, LDL cholesterol, and triglycerides, at lower doses and with comparable tolerability and safety. Prospective studies may be needed to determine whether there are significant benefits of one particular statin in pediatric heart transplantation. The present study has several recognized limitations. The detection of CAV was limited to angiographic assessment and post-mortem examinations. As such less severe degrees of CAV as can be detected by intravascular ultrasound were not reported. In addition, the administration of pravastatin was not randomized. In summary pravastatin therapy was associated with a significant reduction in CAV in pediatric heart transplant recipients. We believe that statin therapy should be administered routinely in following heart transplantation in children. Further studies are warranted to better understand the coronary-protective effects in children, especially those with normal lipid profiles. REFERENCES 1. Fraund S, Pethig K, Franke U, et al. Ten year survival after heart transplantation: palliative procedure or successful longterm treatment? Heart 1999;82:47–51.
The Journal of Heart and Lung Transplantation January 2005
2. Kobashigawa JA, Katznelson S, Laks H, et al. Effect of pravastatin on outcomes after cardiac transplantation. N Engl J Med 1995;333:621–7. 3. Wenke K, Meiser B, Thiery J, et al. Simvastastin reduces graft vessel disease and mortality after heart transplantation: a four-year randomized trial. Circulation 1997;96: 1398 –402. 4. Shishehbor MH, Brennan ML, Aviles RJ, et al. Statins promote potent systemic antioxidant effects through specific inflammatory pathways. Circulation 2003;108: 426 –31. 5. Katznelson S. Immunosuppressive and antiproliferative effects of HMG-CoA reductase inhibitors. Transplant Proc 1991;31(3B Suppl):22S–24S. 6. Pahl E, Naftel DC, Kuhn MA, Shaddy RE, Morrow R, Kirklin JJ. The incidence of and impact of transplant coronary artery disease in pediatric recipients: a 9 year multi-institutional study (abstr). Circulation 2002;10:II396. 7. Mulla NF, Johnston JK, Vander Dussen L, et al. Late rejection is a predictor of transplant coronary artery disease in children. J Am Coll Cardiol 2001;37:243–50. 8. Addonizio LJ, Hsu DT, Douglas JF, et al. Decreasing incidence of coronary artery disease in pediatric heart transplant recipients using increased immunosuppression. Circulation 1993;88(5 Pt 2):II224 –9. 9. Hirsch R, Balzer DT, Dent CL, Huddleston CB, Mendeloff EN, Canter CE. Outcome after diagnosis of moderatesevere transplant coronary artery disease (TCAD) in pediatric heart transplant recipients. J Heart Lung Transplant 2001;20:261–2. 10. Crowley J, Hu M. Covariance analysis of heart transplant survival data. J Am Stat Assoc 1977;72:27–36. 11. Penson MG, Fricker FJ, Thompson JR, et al. Safety and efficacy of pravastatin therapy for the prevention of hyperlipidemia in pediatric and adolescent cardiac transplant recipients. J Heart Lung Transplant 200;20: 611– 8. 12. Chin C, Gamberg P, Miller J, Luikart H, Bernstein D. Efficacy and safety of atorvastatin after pediatric heart transplantation. J Heart Lung Transplant 2002;21:1213–7. 13. See VY, Jr, DeNofrio D, Goldberg L, et al. Effect of atorvastatin on postcardiac transplant increase in lowdensity lipoprotein cholesterol reduces development of intimal hyperplasia and progression of endothelial dysfunction. Am J Cardiol 2003;92:11–5. 14. Sadeghi MM, Tiglio A, Sadigh K, et al. Inhibition of interferon-gamma-mediated microvascular endothelial cell major histocompatibility complex class II gene activation by HMG-CoA reductase inhibitors. Transplantation 2001;71:1262–8. 15. Magnani G, Carinci V, Magelli C, Potena L, Reggiani LB, Branzi A. Role of statins in the management of dyslipidemia after cardiac transplant: randomized controlled trial comparing the efficacy and the safety of atorvastatin with pravastatin. J Heart Lung Transplant 2000;19: 710 –5.