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Cardiac Allograft Vasculopathy Compared by Intravascular Ultrasound Sonography: Everolimus to Mycophenolate Mofetil—One Single-Center Experience
Cardiac Allograft Vasculopathy Compared by Intravascular Ultrasound Sonography: Everolimus to Mycophenolate Mofetil—One Single-Center Experience N.-K. Chou, C.-F. Jan, N.-H. Chi, C.-M. Lee, I.-H. Wu, S.-C. Huang, Y.-S. Chen, H.-Y. Yu, C.-I. Tsao, W.-J. Ko, S.-H. Chu, and S.-S. Wang ABSTRACT Cardiac allograft vasculopathy (CAV) remains one of the leading causes of late graft failure and death. Cyclosporine microemulsion Neoral (CsA) had been used in heart transplantation (HTx) recipients. Meanwhile, Everolimus (EVL; Certican, Norvatis Pharmaceuticals; Basel, Switzerland) or mycophenolate mofetil (MMF) have been combined with CsA for maintenance treatment. We compared atherosclerosis in HTx patients showing CAV by intravascular ultrasound (IVUS) in two groups: the CE who received CsA, EVL, and steroid versus the CM group, who received CsA, MMF, and steroid. Materials and methods. We explored IVUS parameters such as plaque thickness (PT), lumen circumference (LC), media adventitial circumference, lumen diameter (LD), and media adventitial diameter to characterize the atherosclerosis among CE versus CM groups. Results. In this study, both the CE and CM groups showed increased plaque thickening in the first year posttransplantation (P ⬍ .05). However, MMF significantly reduced LC and LD (P ⬍ .05) Upon multivariate linear regression analysis, the CE group seemed to show less effect on the maximal difference in PT between 2 and 12 months after adjusting for age at transplantation and gender (P ⬍ .05). There was no acute clinical adverse event of CAV reported in either both group during the follow-up. The atherosclerosis of CAV revealed by LC, LDmax, and LDmin was significantly less among patients treated with CE than CM. Conclusion. These results suggested that everolimus-treated patients showed benefits compared with MMF-treated subjects as extrapolated from these IVUS data. VEROLIMUS (EVL; Certican, Norvatis Pharmaceuticals; Basel, Switzerland), may provide benefits to reduce acute rejection episodes and coronary artery vasculopathy (CAV) in heart transplantation (HTx).1 EVL is an antiproliferative drug that blocks the cell cycle via complexing with the immunophilin FK-binding protein 12 to inhibit the protein kinase mammalian target of rapamycin.2 In our previous study,3,4 however, we observed that the trough level (C0) of cyclosporine microemulsion Neoral (CsA) showed a better correlation with area-under-curve than C2 among Chinese heart transplant (HTx) recipients treated with CsA plus azathioprine or mycophenolate mofetil (MMF) or C4 with CsA plus EVL. The trough level appeared to still be a reliable, convenient method for
E
© 2012 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 44, 897– 899 (2012)
therapeutic drug monitoring. The fractional flow reserve and coronary flow reserve (CFR), indices of epicardial and resistance vessel integrity respectively have been used to investigate the functional relevance of CAV.5,6 From the Department of Surgery (N.-K.C., N.-H.C., I.-H.W., S.-C.H., Y.-S.C., H.-Y.Y., C.-I.T., W.-J.K., S.-H.C., S.-S.W.) Family Medicine (C.-F.J.), and Internal Medicine (C.-M.L.), National Taiwan University Hospital, Taipei, Taiwan. This work was supported in part by the Department of Medical Research of National Taiwan University Hospital. Address reprint requests to Shoei-Shen Wang, MD, PhD, Department of Surgery, National Taiwan University Hospital, No. 7 Chung-Shan South Road, Taipei, Taiwan. E-mail: wangp@ ntu.edu.tw 0041-1345/–see front matter doi:10.1016/j.transproceed.2012.03.041 897
898
CHOU, JAN, CHI ET AL Table 1. Baseline Demographics of Heart Transplant Recipients CE Group (n ⫽ 16)
Age (years): mean (range) Male sex, n (%) Cause of heart failure, n (%) Dilated cardiomyopathy Ischemic cardiomyopathy Other
45 (30–60) 14 (87.5%) 10 (62.5%) 5 (31.25%) 1 (6.25%)
CM Group (n ⫽ 8)
51 (31–67) 6 (75%) 7 (87.5%) 1 (12.5%) 0 (0%)
CE group received cyclosporine, everolimus, and steroid; CM group received cyclosporine, mycophenolate mofetil, and steroid.
The impairment of microvascular integrity as assessed by CFR was shown to correlate with plaque burden as measured by Intravascular ultrasonography (IVUS) in our previous reports of HTx patients showing physiologically normal epicardial coronary arteries. This observation indicated concordant involvement of epicardial and resistance vessels in early CAV.7 In the present study we compared EVL and MMF in HTx recipients with CAV using IVUS.
MATERIALS AND METHODS From 2006 to 2010, we enrolled 24 HTx patients who signed informed written consents. The subjects were assigned to a CE group, who received CsA, EVL, and steroid (n ⫽ 16), or a CM group, who received CsA, MMF, and steroid (n ⫽ 8). The baseline demographic data were similar between the groups (Table 1). After transplantation, routine monitoring was performed in all patients, including biochemical tests, complete cell counts, cytomegalovirus monitoring, and echocardiographic examinations. Protocol endomyocardial biopsy and IVUS were performed: the baseline IVUS at 6 weeks (minimum) and the followup at month 12 posttransplantation. All IVUS parameters were expressed as the differentials of plaque thickness (PT) lumen circumference (LC), media adventitial circumference, lumen diameter (LD), and media adventitial diameter. IVUS was thus used to demonstrate the severity and incidence of CAV in the CE compared with the CM group. The data were expressed as mean values with standard deviations. Paired Student t tests (SAS 9.2) were used for between-group comparisons.
RESULTS
Plaque thickening was noted in both CE and CM groups in the first year posttransplantation. In the CE group, the PTmax increased 0.0455 ⫾ 0.0177 mm, (P ⫽ .0214) and the PTmin increased 0.028 ⫾ 0.0425 mm (P ⫽ .0187). In the CM group, the PTmax increased 0.1548 ⫾ 0.1423 mm (P ⫽ .0179) and the PTmin increased 0.0629 ⫾ 0.0549 mm (P ⫽ .0143) while the LC decreased 1.229 ⫾ 0.753 mm (P ⫽ .0024). The LDmax decreased 0.359 ⫾ 0.2961 mm (P ⫽ .011) and the LDmin decreased 0.411 ⫾ 0.204 (P ⫽ .0037; Table 2). Upon multivariate linear regression analysis, the CE compared with the CM group seemed to show a lesser PTmax difference after the second month after adjusting for age at transplantation and gender (P ⬍ .05). However, the effect was not seen in PTmin. There was no acute clinical adverse event of CAV reported in either group during the follow-up. DISCUSSION
EVL was significantly more efficacious than azathioprine to prevent vasculopathy among HTx recipients at 12 months.1 Our previous reports showed 5-years outcomes of HTx recipients using EVL, CsA, and steroid to not be inferior to those of MMF, CsA, and steroid.8 The survival after heart transplantation under EVL, CsA, and steroid was good: at 1 year, it 97.67% ⫾ 2.22%, and at 5 years, 80.23% ⫾ 6.87%. The efficacy failure rate was 15.2% within 5 years, including 4.3% acute rejection episodes with hemodynamic compromise and 2.2% antibody-mediated rejection. IVUS is considered to be the most sensitive method to predict outcomes. IVUS studies have suggested that the progression of plaque thickening in the first year after HTx is a surrogate marker for major adverse cardiac events after heart transplantation. However, IVUS only provides anatomic information on epicardial coronary arteries and is unable to detect microvascular lesions because of the transducer’s size.9 Furthermore, correlations among IVUS, CFR, and single-photon emission computed tomography abnormalities are inconclusive with respect to prediction of graft failure. Previous studies have yielded conflicting re-
Table 2. The Comparison Between CE and CM Groups by the Parameters of IVUS CE Group (n ⫽ 16)
PTmax PTmin LC MAC LDmax LDmin MADmax MADmin
CM Group (n ⫽ 8)
Mean ⫾ Std Dev
Std Err
P Value
Mean ⫾ Std Dev
Std Err
P Value
0.0455 ⫾ 0.0708 0.028 ⫾ 0.0425 ⫺0.219 ⫾ 0.6869 ⫺0.059 ⫾ 0.6966 ⫺0.076 ⫾ 0.1744 ⫺0.053 ⫾ 0.323 ⫺0.899 ⫾ 3.523 ⫺0.004 ⫾ 0.3239
0.0177 0.0106 0.1717 0.1742 0.0436 0.0807 0.8807 0.081
.0214* .0187* .2222 .74715 .0998 .5187 .3233 .9657
0.1548 ⫾ 0.1423 0.0629 ⫾ 0.0549 ⫺1.229 ⫾ 0.753 ⫺0.497 ⫾ 0.92 ⫺0.359 ⫾ 0.2961 ⫺0.411 ⫾ 0.204 ⫺0.134 ⫾ 0.3609 0.2489 ⫾ 1.3178
0.0503 0.0194 0.2662 0.3253 0.1047 0.0721 0.1276 0.4659
.0179* .0143* .0024* .17 .011* .0037* .3301 .6097
CE group: CsA and EVL; CM group: CsA and MMF; PTmax, plaque thickness maximum (mm); PTmin, plaque thickness minimum (mm); LC, lumen circumference (mm); MAC, media adventitial circumference; LDmax, lumen diameter maximum (mm); LDmin, lumen diameter minimum (mm); MADmax, media advential diameter maximum; MADmin, media advential diameter minimum; Std Dev, standard deviation; Std Err, standard error; IVUS, intravascular ultrasound; CsA, cyclosporine; EVL, evrolimus; CsA, cyclosporine; MMF, mycophenolate mofetil.
CARDIAC ALLOGRAFT VASCULOPATHY
sults as to whether epicardial and microvascular diseases occur concordantly in CAV.7,10 IVUS has been shown to provide useful prognostic information to detect early CAV, by comparing changes in maximal intimal thickness from baseline to 1 year posttransplant.11 In the CE group, the PTmax and the PTmin increased significantly. In the CM group, the PTmax and the PTmin increased; the LC as well as the LD max and LDmin decreased significantly. The atherosclerosis of CAV as reflected by IVUS parameters of LC, LDmax, and LDmin were significantly less decreased in the CE than the CM group. In conclusion, the results using IVUS suggested that EVL-treated patients showed benefits in LC, LDmax, and LDmin compared with MMF-treated subjects. ACKNOWLEDGMENTS The authors acknowledge the collaboration of organ transplantation team at the National Taiwan University Hospital.
REFERENCES 1. Eisen HJ, Tuzcu MT, Dorent R, et al: Everolimus for the prevention of allograft rejection and vasculopathy in cardiac transplant recipients. N Engl J Med 349:847, 2003 2. Kirchner GI, Meier-Wiedenbach I, Manns MP: Clinical pharmacokinetics of everolimus. Clin Pharmacokinet 43:83, 2004 3. Wang CH, Ko WJ, Chou NK, et al: A limited sampling strategy for the estimation of 12-hour cyclosporine Neoral area
899 under the curve in Chinese cardiac transplant recipients. Transplant Proc 36:2390, 2004 4. Wang CH, Chou NK, Wu F-L L, et al: Therapeutic drug monitoring of cyclosporine Neoral in de novo Chinese cardiac transplant recipients treated with and everolimus-cyclosporine immunosuppressive regimen. Transplant Proc 38:2132, 2006 5. Pijls NH, De Bruyne B, Smith L, et al: Coronary thermodilution to assess flow reserve: validation in humans. Circulation 105:2482, 2002 6. Weis M, Hartmann A, Olbrich HG, et al: Prognostic significance of coronary flow reserve on left ventricular ejection fraction in cardiac transplant recipients. Transplantation 65:103, 1998 7. Lee CM, Wu YW, Jui HY, et al: Intravascular ultrasound correlates with coronary flow reserve and predicts the survival in angiographically normal cardiac transplant recipients. Cardiology 109:93, 2008 8. Wang SS, Chou NK, Chi NH, et al: The survival of heart transplant recipients using cyclosporine and everolimus is not inferior to that using cyclosporine and ⫹ mycophenolate. Transplant Proc 42:938, 2010 9. Fearon WF, Yeung AC: Evaluating intermediate coronary lesions in the cardiac catheterization laboratory. Rev Cardiovasc Med 4:1, 2003 10. Fearon WF, Hirohata A, Nakamura M, et al: Discordant changes in epicardial and microvascular coronary physiology after cardiac transplantation: Physiologic Investigation for Transplant Arteriopathy II (PITA II) study. J Heart Lung Transplant 25:765, 2006 11. Kobashigawa JA, Katznelson S, Laks H, et al: Effect of pravastatin on outcomes after cardiac transplantation. N Engl J Med 333:621, 1995
E
© 2012 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 44, 897– 899 (2012)
therapeutic drug monitoring. The fractional flow reserve and coronary flow reserve (CFR), indices of epicardial and resistance vessel integrity respectively have been used to investigate the functional relevance of CAV.5,6 From the Department of Surgery (N.-K.C., N.-H.C., I.-H.W., S.-C.H., Y.-S.C., H.-Y.Y., C.-I.T., W.-J.K., S.-H.C., S.-S.W.) Family Medicine (C.-F.J.), and Internal Medicine (C.-M.L.), National Taiwan University Hospital, Taipei, Taiwan. This work was supported in part by the Department of Medical Research of National Taiwan University Hospital. Address reprint requests to Shoei-Shen Wang, MD, PhD, Department of Surgery, National Taiwan University Hospital, No. 7 Chung-Shan South Road, Taipei, Taiwan. E-mail: wangp@ ntu.edu.tw 0041-1345/–see front matter doi:10.1016/j.transproceed.2012.03.041 897
898
CHOU, JAN, CHI ET AL Table 1. Baseline Demographics of Heart Transplant Recipients CE Group (n ⫽ 16)
Age (years): mean (range) Male sex, n (%) Cause of heart failure, n (%) Dilated cardiomyopathy Ischemic cardiomyopathy Other
45 (30–60) 14 (87.5%) 10 (62.5%) 5 (31.25%) 1 (6.25%)
CM Group (n ⫽ 8)
51 (31–67) 6 (75%) 7 (87.5%) 1 (12.5%) 0 (0%)
CE group received cyclosporine, everolimus, and steroid; CM group received cyclosporine, mycophenolate mofetil, and steroid.
The impairment of microvascular integrity as assessed by CFR was shown to correlate with plaque burden as measured by Intravascular ultrasonography (IVUS) in our previous reports of HTx patients showing physiologically normal epicardial coronary arteries. This observation indicated concordant involvement of epicardial and resistance vessels in early CAV.7 In the present study we compared EVL and MMF in HTx recipients with CAV using IVUS.
MATERIALS AND METHODS From 2006 to 2010, we enrolled 24 HTx patients who signed informed written consents. The subjects were assigned to a CE group, who received CsA, EVL, and steroid (n ⫽ 16), or a CM group, who received CsA, MMF, and steroid (n ⫽ 8). The baseline demographic data were similar between the groups (Table 1). After transplantation, routine monitoring was performed in all patients, including biochemical tests, complete cell counts, cytomegalovirus monitoring, and echocardiographic examinations. Protocol endomyocardial biopsy and IVUS were performed: the baseline IVUS at 6 weeks (minimum) and the followup at month 12 posttransplantation. All IVUS parameters were expressed as the differentials of plaque thickness (PT) lumen circumference (LC), media adventitial circumference, lumen diameter (LD), and media adventitial diameter. IVUS was thus used to demonstrate the severity and incidence of CAV in the CE compared with the CM group. The data were expressed as mean values with standard deviations. Paired Student t tests (SAS 9.2) were used for between-group comparisons.
RESULTS
Plaque thickening was noted in both CE and CM groups in the first year posttransplantation. In the CE group, the PTmax increased 0.0455 ⫾ 0.0177 mm, (P ⫽ .0214) and the PTmin increased 0.028 ⫾ 0.0425 mm (P ⫽ .0187). In the CM group, the PTmax increased 0.1548 ⫾ 0.1423 mm (P ⫽ .0179) and the PTmin increased 0.0629 ⫾ 0.0549 mm (P ⫽ .0143) while the LC decreased 1.229 ⫾ 0.753 mm (P ⫽ .0024). The LDmax decreased 0.359 ⫾ 0.2961 mm (P ⫽ .011) and the LDmin decreased 0.411 ⫾ 0.204 (P ⫽ .0037; Table 2). Upon multivariate linear regression analysis, the CE compared with the CM group seemed to show a lesser PTmax difference after the second month after adjusting for age at transplantation and gender (P ⬍ .05). However, the effect was not seen in PTmin. There was no acute clinical adverse event of CAV reported in either group during the follow-up. DISCUSSION
EVL was significantly more efficacious than azathioprine to prevent vasculopathy among HTx recipients at 12 months.1 Our previous reports showed 5-years outcomes of HTx recipients using EVL, CsA, and steroid to not be inferior to those of MMF, CsA, and steroid.8 The survival after heart transplantation under EVL, CsA, and steroid was good: at 1 year, it 97.67% ⫾ 2.22%, and at 5 years, 80.23% ⫾ 6.87%. The efficacy failure rate was 15.2% within 5 years, including 4.3% acute rejection episodes with hemodynamic compromise and 2.2% antibody-mediated rejection. IVUS is considered to be the most sensitive method to predict outcomes. IVUS studies have suggested that the progression of plaque thickening in the first year after HTx is a surrogate marker for major adverse cardiac events after heart transplantation. However, IVUS only provides anatomic information on epicardial coronary arteries and is unable to detect microvascular lesions because of the transducer’s size.9 Furthermore, correlations among IVUS, CFR, and single-photon emission computed tomography abnormalities are inconclusive with respect to prediction of graft failure. Previous studies have yielded conflicting re-
Table 2. The Comparison Between CE and CM Groups by the Parameters of IVUS CE Group (n ⫽ 16)
PTmax PTmin LC MAC LDmax LDmin MADmax MADmin
CM Group (n ⫽ 8)
Mean ⫾ Std Dev
Std Err
P Value
Mean ⫾ Std Dev
Std Err
P Value
0.0455 ⫾ 0.0708 0.028 ⫾ 0.0425 ⫺0.219 ⫾ 0.6869 ⫺0.059 ⫾ 0.6966 ⫺0.076 ⫾ 0.1744 ⫺0.053 ⫾ 0.323 ⫺0.899 ⫾ 3.523 ⫺0.004 ⫾ 0.3239
0.0177 0.0106 0.1717 0.1742 0.0436 0.0807 0.8807 0.081
.0214* .0187* .2222 .74715 .0998 .5187 .3233 .9657
0.1548 ⫾ 0.1423 0.0629 ⫾ 0.0549 ⫺1.229 ⫾ 0.753 ⫺0.497 ⫾ 0.92 ⫺0.359 ⫾ 0.2961 ⫺0.411 ⫾ 0.204 ⫺0.134 ⫾ 0.3609 0.2489 ⫾ 1.3178
0.0503 0.0194 0.2662 0.3253 0.1047 0.0721 0.1276 0.4659
.0179* .0143* .0024* .17 .011* .0037* .3301 .6097
CE group: CsA and EVL; CM group: CsA and MMF; PTmax, plaque thickness maximum (mm); PTmin, plaque thickness minimum (mm); LC, lumen circumference (mm); MAC, media adventitial circumference; LDmax, lumen diameter maximum (mm); LDmin, lumen diameter minimum (mm); MADmax, media advential diameter maximum; MADmin, media advential diameter minimum; Std Dev, standard deviation; Std Err, standard error; IVUS, intravascular ultrasound; CsA, cyclosporine; EVL, evrolimus; CsA, cyclosporine; MMF, mycophenolate mofetil.
CARDIAC ALLOGRAFT VASCULOPATHY
sults as to whether epicardial and microvascular diseases occur concordantly in CAV.7,10 IVUS has been shown to provide useful prognostic information to detect early CAV, by comparing changes in maximal intimal thickness from baseline to 1 year posttransplant.11 In the CE group, the PTmax and the PTmin increased significantly. In the CM group, the PTmax and the PTmin increased; the LC as well as the LD max and LDmin decreased significantly. The atherosclerosis of CAV as reflected by IVUS parameters of LC, LDmax, and LDmin were significantly less decreased in the CE than the CM group. In conclusion, the results using IVUS suggested that EVL-treated patients showed benefits in LC, LDmax, and LDmin compared with MMF-treated subjects. ACKNOWLEDGMENTS The authors acknowledge the collaboration of organ transplantation team at the National Taiwan University Hospital.
REFERENCES 1. Eisen HJ, Tuzcu MT, Dorent R, et al: Everolimus for the prevention of allograft rejection and vasculopathy in cardiac transplant recipients. N Engl J Med 349:847, 2003 2. Kirchner GI, Meier-Wiedenbach I, Manns MP: Clinical pharmacokinetics of everolimus. Clin Pharmacokinet 43:83, 2004 3. Wang CH, Ko WJ, Chou NK, et al: A limited sampling strategy for the estimation of 12-hour cyclosporine Neoral area
899 under the curve in Chinese cardiac transplant recipients. Transplant Proc 36:2390, 2004 4. Wang CH, Chou NK, Wu F-L L, et al: Therapeutic drug monitoring of cyclosporine Neoral in de novo Chinese cardiac transplant recipients treated with and everolimus-cyclosporine immunosuppressive regimen. Transplant Proc 38:2132, 2006 5. Pijls NH, De Bruyne B, Smith L, et al: Coronary thermodilution to assess flow reserve: validation in humans. Circulation 105:2482, 2002 6. Weis M, Hartmann A, Olbrich HG, et al: Prognostic significance of coronary flow reserve on left ventricular ejection fraction in cardiac transplant recipients. Transplantation 65:103, 1998 7. Lee CM, Wu YW, Jui HY, et al: Intravascular ultrasound correlates with coronary flow reserve and predicts the survival in angiographically normal cardiac transplant recipients. Cardiology 109:93, 2008 8. Wang SS, Chou NK, Chi NH, et al: The survival of heart transplant recipients using cyclosporine and everolimus is not inferior to that using cyclosporine and ⫹ mycophenolate. Transplant Proc 42:938, 2010 9. Fearon WF, Yeung AC: Evaluating intermediate coronary lesions in the cardiac catheterization laboratory. Rev Cardiovasc Med 4:1, 2003 10. Fearon WF, Hirohata A, Nakamura M, et al: Discordant changes in epicardial and microvascular coronary physiology after cardiac transplantation: Physiologic Investigation for Transplant Arteriopathy II (PITA II) study. J Heart Lung Transplant 25:765, 2006 11. Kobashigawa JA, Katznelson S, Laks H, et al: Effect of pravastatin on outcomes after cardiac transplantation. N Engl J Med 333:621, 1995