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Single Nucleotide Polymorphisms, SNPs, Associated With the Efficacy and Security of Immunosuppressive Treatment in Heart Transplantation
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The Journal of Heart and Lung Transplantation, Vol 32, No 4S, April 2014
Luminex without any prophylactic therapy. The prophylactic treatment of acute humoral rejection consisted of plasmapheresis during 5 post transplantation days followed by IVIg (2 g/kg). The prophylactic immunosuppressive therapy of acute cellular rejection was standardized and similar for both groups. Primary endpoint was the incidence of histologic AMR at 18 months after transplantation. Results: 35 patients were included between 2003-2006 and 29 treated patients were transplanted between 2007-2010 . At 18 months, histologic data were available for 26 untreated and 24 treated patients. The rate of histologic AMR was 44% (n= 22) and was significantly lower in the treated group (n= 7, 29%) than the untreated group (n= 15, 58%, p= 0.046) (Figure 1). Conclusion: Prophylactic therapy of AMR by Plasmapheresis and IVIg decrease significantly the incidence of histologic AMR. Further investigation are underway to assess the benefit of this prophylactic strategy on the mortality and the incidence of cardiac allograft vasculopathy.
3( 85) Single Nucleotide Polymorphisms, SNPs, Associated With the Efficacy and Security of Immunosuppressive Treatment in Heart Transplantation I. Sanchez-Lazaro ,1 C. Jordán-de Luna,2 L. Almenar-Bonet,1 M. Herrero-Cervera,2 V. Boso-Ribelles,2 S. Aliño-Pellicer,2 L. Martinez-Dolz,1 J. Poveda-Andres,2 A. Salvador-Sanz.1 1Cardiology Department. Hert Failure and Transplantation Unit, Hospital Universitari i Politècnic La Fe, Valencia, Spain; 2Pharmacy Department, Hospital Universitari i Politècnic La Fe, Valencia, Spain. Purpose: Interindividual variability in the response to drugs can be partially explained by Pharmacogenetics, which correlates the presence of genetic variants (as SNPS) with drug blood levels, efficacy or adverse effects. In Transplantation, many relevant results have been obtained but there are still few cause-effect correlations relating efficacy and security of immunosuppressive treatment. Methods: In 60 heart transplant patients, treated with tacrolimus or cyclosporine as calcineurin inhibitor, we analyzed a panel of 36 SNPs in the main genes related with transport and metabolisms of these drugs. A single blood sample of each patient was used for genotyping with MassArray, from Sequenom. Genotyping data were correlated with clinical data of those patientes follow up during the first year post-transplantation regarding: 1) rejection presence/absence; 2) infections presence/absence; 3) renal function, calculated by Cockroft and MDRD methods. The results for each of the 36 SNPs were analyzed by Χ 2 or Fisher’s exact tests for variables 1 and 2; twoway ANOVA was employed for variable 3, only taking into consideration the significant correlations (p≤ 0.05). Results: A significant increase in organ rejection (p= 0.049) was correlated with SNP rs2066844 in NOD2/CARD15 gene (76,1% patients CC vs. 33,3% CT/TT), a gene related to lymphocyte activation. The existence of infections was correlated with SNP rs1128503 in ABCB1 gene (p= 0.015), which codes for the transporter of calcineurin inhibitors, glicoproteinP. Here, the variant CC reduces the probability of infections to a 50%. This variant was also directly associated with lower drug blood levels (cyclosporine as well as tacrolimus), expressed as trough level corrected by dose and patient’s weight, Cmin/(dose/weight). Regarding renal function, we found significantly lower levels in patients AG in rs9282564, again from ABCB1 gene, in contrast to
patients AA (25% reduction with p= 0.04 for Cockroft, and 32% reduction with p= 0.002 for MDRD). Conclusion: Pharmacogenetic studies can help to identify patients at higher risk of suffering infections, renal dysfunction and rejection under the treatment with calcineurin inhibitors in heart transplantation. 3( 86) Long-Term Therapy with Everolimus: Promising Results at Three Years of the CERTIC Registry L. Potena ,1 R. Fiocchi,2 C. Maiello,3 A. D’Armini,4 G. Gerosa,5 M. Rinaldi,6 M. Maccherini,7 U. Livi,8 M. Frigerio,9 D. Colombo,10 R. Brusa,10 F. Parisi.11 1Cardiovascular Department, University of Bologna, Bologna, Italy; 2Papa Giovanni XXIII Hospital, Bergamo, Italy; 3Monaldi Hospital - II Università di Napoli, Napoli, Italy; 4San Matteo Hospital, Pavia, Italy,; 5University Hospital of Padova, Padova, Italy; 6San Giovanni Battista Hospital, Torino, Italy; 7Policlinico Santa Maria alle Scotte, Siena, Italy; 8Santa Maria della Misericordia Hospital, Udine, Italy; 9Niguarda - Ca’ Granda Hospital, Milano, Italy; 10Novartis Farma, Origgio (VA), Italy; 11Bambin Gesù Hospital, Roma, Italy. Purpose: Everolimus (EVR) is registered for prevention of acute rejection in kidney and heart transplant (HT) recipients in several countries (in US EVR is not licensed for HT). EVR displays multiple effects potentially associated with benefits in patients with long-term complications, such as malignancies, allograft vasculopathy or renal insufficiency. We designed the CERTIC registry to collect prospective multicenter data on safety and efficacy of long-term use of EVR in de novo and converted patients, with a high comorbidity profile. Methods: Between 2008 and 2010, 781 recipients of renal or HT who were on therapy with EVR for at least 6 months entered this 5-year registry. Herein we report analysis of 3y follow-up data about survival, malignancies, and renal function in the HT recipients’ cohort. Results: 401 HT recipients (of whom 24% started EVR as a de novo strategy) were enrolled; 306 (76%) patients started EVR 8±5y after HT, following renal dysfunction (55%), allograft vasculopathy (21%), or malignancies (13%). Overall, including the period of EVR treatment before study entry, patients had been on EVR for 5±1y. Survival rate was high (90%), with 39 fatal events, 5% in de novo and 11% in conversion patients. Incidence rate of new-onset malignancies under EVR treatment was 1.6% in de novo and 1.4% in conversion patients, excluding non-melanoma skin cancers. No Kaposi’s sarcomas were recorded. Renal function was overall stable during EVR treatment, with 18 patients returning to dialysis (4.5%), all in conversion group. Estimated glomerular filtration rate (eGFR) at study enrollment and at 3y was: 65.7±46.8 and 69.9±44.0 in de novo, p= ns; 56.4±42.1 and 56.1±37.3 in conversion patients, p= ns. EVR introduction in patients with renal function impairment stabilized eGFR levels (44.2±21.0 at conversion and 49.3±32.7 at 3y, p= ns). Conclusion: By picturing real-life clinical practice, this large prospective registry preliminary data on EVR therapy shows promising survival rates both in de novo patients and in those with high-risk comorbidities. Incidence of malignancies is low and renal function seems to be effectively preserved. 3( 87) Heart Failure with Preserved Ejection Fraction Induced Reactive Pulmonary Hypertension Lacks Nitric Oxide Vasoreactivity Similar to Pulmonary Arterial Hypertension J. Salamon ,1 J. Mazurek,2 R. Zolty.1 1Cardiology, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY; 2Cardiology, Hospital of the University of Pennsylania, Philaelphia, PA. Purpose: Recent evidence suggests that > 33% of patients with Heart Failure with Preserved Ejection Fraction induced Pulmonary Hypertension (HFpEF-PH) develop an elevated transpulmonary gradient (TPG; aka HFpEF-rPH) similar to Pulmonary Arterial Hypertension (PAH). > 85% of patients with PAH lack acute Nitric Oxide (NO) vasoreactivity (mPAP drop > 10mmHg and PVR drop > 33%). However, the immediate hemodynamic (HD) response to inhaled NO in HFpEF-rPH has yet to be fully evaluated or compared to PAH. Methods: Prior to initiation of treatment, right heart cath and echo (TTE) were performed in patients referred to our PH clinic. Patients received 5
The Journal of Heart and Lung Transplantation, Vol 32, No 4S, April 2014
Luminex without any prophylactic therapy. The prophylactic treatment of acute humoral rejection consisted of plasmapheresis during 5 post transplantation days followed by IVIg (2 g/kg). The prophylactic immunosuppressive therapy of acute cellular rejection was standardized and similar for both groups. Primary endpoint was the incidence of histologic AMR at 18 months after transplantation. Results: 35 patients were included between 2003-2006 and 29 treated patients were transplanted between 2007-2010 . At 18 months, histologic data were available for 26 untreated and 24 treated patients. The rate of histologic AMR was 44% (n= 22) and was significantly lower in the treated group (n= 7, 29%) than the untreated group (n= 15, 58%, p= 0.046) (Figure 1). Conclusion: Prophylactic therapy of AMR by Plasmapheresis and IVIg decrease significantly the incidence of histologic AMR. Further investigation are underway to assess the benefit of this prophylactic strategy on the mortality and the incidence of cardiac allograft vasculopathy.
3( 85) Single Nucleotide Polymorphisms, SNPs, Associated With the Efficacy and Security of Immunosuppressive Treatment in Heart Transplantation I. Sanchez-Lazaro ,1 C. Jordán-de Luna,2 L. Almenar-Bonet,1 M. Herrero-Cervera,2 V. Boso-Ribelles,2 S. Aliño-Pellicer,2 L. Martinez-Dolz,1 J. Poveda-Andres,2 A. Salvador-Sanz.1 1Cardiology Department. Hert Failure and Transplantation Unit, Hospital Universitari i Politècnic La Fe, Valencia, Spain; 2Pharmacy Department, Hospital Universitari i Politècnic La Fe, Valencia, Spain. Purpose: Interindividual variability in the response to drugs can be partially explained by Pharmacogenetics, which correlates the presence of genetic variants (as SNPS) with drug blood levels, efficacy or adverse effects. In Transplantation, many relevant results have been obtained but there are still few cause-effect correlations relating efficacy and security of immunosuppressive treatment. Methods: In 60 heart transplant patients, treated with tacrolimus or cyclosporine as calcineurin inhibitor, we analyzed a panel of 36 SNPs in the main genes related with transport and metabolisms of these drugs. A single blood sample of each patient was used for genotyping with MassArray, from Sequenom. Genotyping data were correlated with clinical data of those patientes follow up during the first year post-transplantation regarding: 1) rejection presence/absence; 2) infections presence/absence; 3) renal function, calculated by Cockroft and MDRD methods. The results for each of the 36 SNPs were analyzed by Χ 2 or Fisher’s exact tests for variables 1 and 2; twoway ANOVA was employed for variable 3, only taking into consideration the significant correlations (p≤ 0.05). Results: A significant increase in organ rejection (p= 0.049) was correlated with SNP rs2066844 in NOD2/CARD15 gene (76,1% patients CC vs. 33,3% CT/TT), a gene related to lymphocyte activation. The existence of infections was correlated with SNP rs1128503 in ABCB1 gene (p= 0.015), which codes for the transporter of calcineurin inhibitors, glicoproteinP. Here, the variant CC reduces the probability of infections to a 50%. This variant was also directly associated with lower drug blood levels (cyclosporine as well as tacrolimus), expressed as trough level corrected by dose and patient’s weight, Cmin/(dose/weight). Regarding renal function, we found significantly lower levels in patients AG in rs9282564, again from ABCB1 gene, in contrast to
patients AA (25% reduction with p= 0.04 for Cockroft, and 32% reduction with p= 0.002 for MDRD). Conclusion: Pharmacogenetic studies can help to identify patients at higher risk of suffering infections, renal dysfunction and rejection under the treatment with calcineurin inhibitors in heart transplantation. 3( 86) Long-Term Therapy with Everolimus: Promising Results at Three Years of the CERTIC Registry L. Potena ,1 R. Fiocchi,2 C. Maiello,3 A. D’Armini,4 G. Gerosa,5 M. Rinaldi,6 M. Maccherini,7 U. Livi,8 M. Frigerio,9 D. Colombo,10 R. Brusa,10 F. Parisi.11 1Cardiovascular Department, University of Bologna, Bologna, Italy; 2Papa Giovanni XXIII Hospital, Bergamo, Italy; 3Monaldi Hospital - II Università di Napoli, Napoli, Italy; 4San Matteo Hospital, Pavia, Italy,; 5University Hospital of Padova, Padova, Italy; 6San Giovanni Battista Hospital, Torino, Italy; 7Policlinico Santa Maria alle Scotte, Siena, Italy; 8Santa Maria della Misericordia Hospital, Udine, Italy; 9Niguarda - Ca’ Granda Hospital, Milano, Italy; 10Novartis Farma, Origgio (VA), Italy; 11Bambin Gesù Hospital, Roma, Italy. Purpose: Everolimus (EVR) is registered for prevention of acute rejection in kidney and heart transplant (HT) recipients in several countries (in US EVR is not licensed for HT). EVR displays multiple effects potentially associated with benefits in patients with long-term complications, such as malignancies, allograft vasculopathy or renal insufficiency. We designed the CERTIC registry to collect prospective multicenter data on safety and efficacy of long-term use of EVR in de novo and converted patients, with a high comorbidity profile. Methods: Between 2008 and 2010, 781 recipients of renal or HT who were on therapy with EVR for at least 6 months entered this 5-year registry. Herein we report analysis of 3y follow-up data about survival, malignancies, and renal function in the HT recipients’ cohort. Results: 401 HT recipients (of whom 24% started EVR as a de novo strategy) were enrolled; 306 (76%) patients started EVR 8±5y after HT, following renal dysfunction (55%), allograft vasculopathy (21%), or malignancies (13%). Overall, including the period of EVR treatment before study entry, patients had been on EVR for 5±1y. Survival rate was high (90%), with 39 fatal events, 5% in de novo and 11% in conversion patients. Incidence rate of new-onset malignancies under EVR treatment was 1.6% in de novo and 1.4% in conversion patients, excluding non-melanoma skin cancers. No Kaposi’s sarcomas were recorded. Renal function was overall stable during EVR treatment, with 18 patients returning to dialysis (4.5%), all in conversion group. Estimated glomerular filtration rate (eGFR) at study enrollment and at 3y was: 65.7±46.8 and 69.9±44.0 in de novo, p= ns; 56.4±42.1 and 56.1±37.3 in conversion patients, p= ns. EVR introduction in patients with renal function impairment stabilized eGFR levels (44.2±21.0 at conversion and 49.3±32.7 at 3y, p= ns). Conclusion: By picturing real-life clinical practice, this large prospective registry preliminary data on EVR therapy shows promising survival rates both in de novo patients and in those with high-risk comorbidities. Incidence of malignancies is low and renal function seems to be effectively preserved. 3( 87) Heart Failure with Preserved Ejection Fraction Induced Reactive Pulmonary Hypertension Lacks Nitric Oxide Vasoreactivity Similar to Pulmonary Arterial Hypertension J. Salamon ,1 J. Mazurek,2 R. Zolty.1 1Cardiology, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY; 2Cardiology, Hospital of the University of Pennsylania, Philaelphia, PA. Purpose: Recent evidence suggests that > 33% of patients with Heart Failure with Preserved Ejection Fraction induced Pulmonary Hypertension (HFpEF-PH) develop an elevated transpulmonary gradient (TPG; aka HFpEF-rPH) similar to Pulmonary Arterial Hypertension (PAH). > 85% of patients with PAH lack acute Nitric Oxide (NO) vasoreactivity (mPAP drop > 10mmHg and PVR drop > 33%). However, the immediate hemodynamic (HD) response to inhaled NO in HFpEF-rPH has yet to be fully evaluated or compared to PAH. Methods: Prior to initiation of treatment, right heart cath and echo (TTE) were performed in patients referred to our PH clinic. Patients received 5