Everolimus in de novo cardiac transplant recipients: 24-month follow-up

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204 DIAGNOSTIC VALUE AND SAFETY OF ENDOMYOCARDIAL BIOPSY IN SELECTED PATIENTS WITH HEART FAILURE W.O. Howe, J.C. Mendez, K. Malinowska, B.A. Pisani, R.C. Lichtenberg, J.A. Robinson, G.M. Mullen, Advanced Heart Failure/Heart Transplant Program, Loyola University Health System, Maywood, IL Background: The routine use of endomyocardial biopsy (EMB) as a diagnostic test in the evaluation of heart failure patients (HFP) is controversial and generally unadvisable because of low diagnostic yield and potential for significant procedural morbidity and mortality. Purpose: Therefore we reviewed our experience with EMB in a large and mostly referral HFP at our tertiary care center. Methods: We retrospectively reviewed 3419 EMB records from 3/1/97 to 2/28/02 and identified 78 (2.3%) HFP, who were screened and referred for EMB by the heart failure specialists. Pre-EMB clinical diagnosis included 55% dilated cardiomyopathy, 14% prior condition (amyloid, sarcoid, lupus), 7% probable myocarditis, 11% ischemia, 6% drug toxicity, 3% hypertrophic cardiomyopathy, 3% constrictive pericarditis, 1% restrictive cardiomyopathy. EMB samples were routinely submitted for light and electron microscopy, immunofluoresence, Congo red and iron staining. Results: There were 44 (56%) men and 34 (44%) women with mean age of 50.5⫾18.5 (13-81) years. EMB results were non-diagnostic in 57 (73.1%) and diagnostic in 21(26.9%). Diagnostic finding consisted of 8 (10.2%) amyloid, 5 (6.4%) drug toxicity, 4 (5.1%) myocarditis, 2 (2.6%) iron overload and 2 (2.6%) immunologic/lupus. In HFP undergoing EMB there were 2 (2.6%) of right ventricular perforations as the major procedural complication. In comparison in 3341 EMB performed routinely in heart transplant recipients there were 4 (0.12%) bleedings/ hematoma, 3 (0.09%) life threatening arrhythmia, 3 (0.09%) carotid puncture and 1 (0.03%) right ventricular perforation. Conclusions: In HFP without established etiology for heart failure, EMB is of diagnostic value in 26.9% of cases. Contrary to prior concerns regarding the safety of the EMB in HFP this diagnostic test can be completed with low procedural morbidity and no mortality. 205 PROGRAF DECREASES PLASMA CHOLESTEROL IN HEART TRANSPLANT RECIPIENTS WITH TREATED BUT PERSISTING MILD DYSLIPIDEMIA: THE CANADIAN MULTICENTER RANDOMIZED TRIAL OF PROGRAF VERSUS NEORAL Michel White, on Behalf of the Canadian Heart Transplant Group, Research Center, Montreal Heart Institute, Montreal, QC, Canada Background: Despite optimal use of lipid-lowering agents, most heart transplant recipients (htx) exhibit persisting dyslipidemia not satisfying the current guidelines. We have initiated a prospective study of Neoral maintenance versus (vs) conversion to Prograf immunoprophylaxis in stable htx exhibiting persistent dyslipidemia despite optimal treatment with lipid-lowering agents. Methods: One hundred and twenty-nine stable htx, aged 56.7⫾10.1 years (mean⫾SD) and 77.9⫾42.2 months post-op. were randomized to continue on Neoral (n⫽64) or switch to Prograf (n⫽65). Complete lipid profile was measured at baseline (bsl) and after 1, 3 and 6 months (6 mo). Hemostatic parameters (fibrinogen, factor VII, VIII, von Willebrand) and proinflammatory markers (hsCRP, homocysteine, sICAM, sVCAM, MCP-I, TPA, PAI-1) were measured at bsl and at 6 mo. Results: The Prograf-treated group exhibited a significant greater decrease in total cholesterol [5.51⫾1.16 (bsl) vs 4.88⫾1.22 mmol/L, (6 mo): Prograf; 5.61⫾1.36 (bsl) vs 5.38⫾0.87 mmol/L (6 mo): Neoral,

The Journal of Heart and Lung Transplantation January 2003 p⫽0.002]. The Prograf group also yielded a significant decrease in LDL-cholesterol [3.10⫾0.8 (bsl) vs 2.72⫾0.88 mmol/L (6 mo); p⫽0.01], and cholesterol/HDL ratio [4.73⫾1.48 (bsl) vs 4.15⫾1.36 (6 mo); p⫽0.02]. The decrease in cholesterol was maximum at one month post-switch. For patients treated with Prograf, the change in plasma creatinine from baseline to month 6 [-6.97⫾25.29 ␮mol/L] was significantly greater than for patients who remained on Neoral [⫹1.13⫾19.53 ␮mol/L] [p⫽0.01]. Blood glucose remains stable in the Prograf-treated patients [5.96⫾1.60 vs 6.01⫾1.87 mmol/L, p⫽0.5]. Conclusions: This large prospective conversion study showed that Prograf provides a significant decrease in total, LDL-cholesterol and cholesterol/HDL ratio as well as an improvement in renal function. These provide a rationale for the use of Prograf in cardiac transplant patients with treated but persisting dyslipidemia.

206 EVEROLIMUS DOSE RECOMMENDATIONS IN DE NOVO HEART TRANSPLANTATION - TDM SIMULATIONS R.C. Starling,1 J. Hare,2 D. Renlund,3 D. Mancini,4 H.W. Mayer,5 H. Schmidli,5 1Transplant Unit, Cleveland Clinic Foundation, Cleveland, OH; 2Transplant Unit, Johns Hopkins, Baltimore, ML; 3 Transplant Unit, Utah Transplant Affiliated Hospitals, Salt Lake City, UT; 4Transplant Unit, Columbia Presbyterian Medical Center, New York, NY; 5BU Transplantation, Novartis Pharma, Basel, Basel, Switzerland Purpose: The role of therapeutic drug monitoring (TDM) in optimizing the use of the proliferation signal inhibitor everolimus was examined in a large heart transplant trial (N⫽634) comparing two doses of everolimus (1.5 and 3 mg/d) vs azathioprine (AZA, 1-3 mg/kg/d) given with CsA microemulsion and corticosteroids. Overall efficacy and intravascular ultrasound (to assess incidence and progression of allograft vasculopathy) was significantly superior for both everolimus doses compared to AZA, while everolimus tolerability was optimal in the 1.5 mg group. Purpose of this investigation was to find the effective trough level concentration of everolimus and to assess the future role of TDM. Method: Cox proportional hazard regression, median-effect, time-toevent analyses and simulations were applied to assess the exposureefficacy relationship, the minimal effective everolimus concentration and the benefit of future TDM. Results: PK/PD analyses suggested that the minimal effective level is 3 ng/mL. The results were robust when looking at events up to 450 days. Patients with an everolimus exposure ⬍3 ng/mL experienced BPAR rates of 44% (AZA 46%), 3-8 ng/mL or ⱖ 8 ng/mL had rates of 24% or 17%, respectively. Kaplan-Meier estimates for the ⬍3, 3-8 and ⱖ 8 ng/mL ranges confirmed these findings; the risk of BPAR for the ⬍ 3 vs. 3-8 ng/mL group was 2.5-fold increased (p⫽0.0001) while 3-8 vs ⱖ 8 ng/mL had the same risk. CsA exposure appeared to have a beneficial influence in reducing early rejections. Creatinine increase was significantly associated to CsA exposure, but not to everolimus exposure. The simulation results suggested that TDM may optimize efficacy and safety by allowing for initial use of 1.5 mg/d with increases in dosage when the trough concentration is below 3 ng/mL.

207 EVEROLIMUS IN DE NOVO CARDIAC TRANSPLANT RECIPIENTS: 24-MONTH FOLLOW-UP A. Haverich,1 E.M. Tuzcu,2 M. Vigano `,3 L. Pulpon,4 R.B. Love,5 R. Dorent,6 H.J. Eisen,7 J. Murphy,8 K.H. Abeywickrama,8

The Journal of Heart and Lung Transplantation Volume 22, Number 1S P. Bernhardt,8 the RADB 253Study Group, 1Med Hochschule, Thoraxchir., Hannover, Germany; 2Cleveland Clinic Foundation, Dept Cardiol, Cleveland, OH; 3Policlinico San Matteo, IRCCS, Pavia, Italy; 4 Clinica Puerta de Hierro, Cardiol., Madrid, Spain; 5University of Wisconsin, Cardiothor.Div., Madison, WI; 6Hopital Pitie Salpetriere, Service Chir., Paris, France; 7Temple University, Cardiol. Sect., Philadelphia, PA; 8Novartis Pharma AG, BU Transplantation, Basel, Switzerland Purpose: A 24-month analysis of an international, double-blind trial comparing the safety and efficacy of everolimus (RAD, Certican™), a novel proliferation inhibitor under development that targets primary causes of chronic rejection, vs AZA in de novo heart transplant recipients. Methods: Patients (N⫽634) were randomised to either RAD 1.5 mg/day (N⫽209), RAD 3 mg/day (N⫽211) or AZA 1-3 mg/kg/day (N⫽214), with cyclosporin microemulsion, steroids and statins. The incidence of efficacy failure (acute rejection (ARJ) ⱖ3A, ARJ with HDC, graft loss, death or lost to follow-up) was determined. Incidence of allograft vasculopathy was assessed by IVUS. Results: Efficacy failure was significantly lower in the RAD 1.5 mg (p⫽0.016) and 3 mg (p⬍0.001) groups vs AZA (incidence: 45.9%, 36% and 57.5%, resp.). The incidence of ARJ was also significantly lower with RAD (1.5 mg: 34.9%, 3 mg: 22.7%, AZA: 48.1%). Patient survival was similar (90%, 86.3% and 88.8%). Viral infections occurred less frequently in both RAD groups, and CMV infection rates were significantly lower (8.6%, 8.1%) than in the AZA group (22.4%). The incidence of bacterial infections was higher with 3 mg RAD (40.3%) vs AZA (25.7%, p⬍0.05) and with 1.5 mg RAD (37.3%, p⬍0.05). Mean serum creatinine was higher in the RAD groups (p⬍0.001). Serum lipids (triglycerides, cholesterol, but not LDL and HDL) were elevated in RAD treated patients (p⬍0.05). The incidence of allograft vasculopathy determined by IVUS is being analysed and will also be presented. Conclusion: Both doses of RAD demonstrated superior efficacy compared to AZA by decreasing the incidence of ARJ as well as the composite endpoint. Overall safety and survival rate were better with 1.5 mg RAD compared to 3 mg. 208 STUDY OF THE SAFETY AND TOLERABILITY OF SIMULECT威 (BASILIXIMAB) VERSUS OKT3 IN HEART TRANSPLANTATION M.G. Crespo-Leiro,1 J.L. Rodriguez-Lambert,2 J.L. Segovia,3 L. Almenar,4 E. Roig,5 M.A. Go ´mez-Sa ´nchez,6 E. Lage,7 N. Manito,8 L.A. Pulpon,3 1Heart Transplant, H.Juan Canalejo, A Coruna, Spain; 2 Heart Transplant, H.Central de Asturias, Oviedo, Spain; 3Heart Transplant, H.Clinica Puerta de Hierro, Madrid, Spain; 4Heart Transplant, H.La Fe, Valencia, Spain; 5Heart Transplant, H.Clinic i Provincial, Barcelona, Spain; 6Heart Transplant, H.12 de Octubre, Madrid, Spain; 7Heart Transplant, H.Virgen del Rocio, Sevilla, Spain; 8 Heart Transplant, H.de Bellvitge, Hospitalet de Llobregat, Barcelona, Spain Purpose: The objective of this study was to assess safety of two types of induction in de novo heart transplantation: Simulect威 (basiliximab) vs OKT3. Methods: 101 adult cardiac allograft receptors were randomized (1:1) to either basiliximab or OKT3, with cyclosporin, MMF and steroids, with 1 year of follow-up. Basiliximab, 40 mg, was administered as i.v. bolus in two doses (day 0 and 4 after transplantation), while OKT3, 5 mg/day, was administered as i.v. bolus from day 0 to 6. Results: Interim results at 3 months are presented. No differences in demographics were observed. The incidence of biopsy confirmed acute

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rejection grade ⱖ3A was similar in both groups (29.2% in basiliximab group and 25.0% in OKT3 group, p⫽ns). The incidence of specific adverse events during first month (i.e. fever, cephalea, acute pumonary edema, hypotension) was observed in more patients in OKT3 (14.69%) than basiliximab (2.17%) group; although this difference was only significant during first week postransplantation (43.75% vs 4.26%, p⬍0.0001). Regarding other reported adverse events, none of them were related to basiliximab compared to 12.8% related to OKT3. The most frequent infection was CMV, which was found in 22.92% of the OKT3 group vs 16.66% of the basiliximab group (p⬍ns). At 3 months, 7 deaths have been reported in OKT3 group vs 3 in basiliximab group (14.6% and 6.3%, respectively; p⫽ns). Conclusions: Preliminary results suggest that Simulect威 (basiliximab) has a similar efficacy and shows a tendency toward a lower incidence of adverse events compared with OKT3. Therefore, it could be a valid alternative for immunosuppressive treatment in de novo heart transplant receptors. 209 THE IMPACT OF PHARMACOGENOMIC FACTORS ON STEROID WEANING IN PEDIATRIC HEART TRANSPLANT PATIENTS USING LOGISTIC REGRESSION ANALYSIS H.X. Zheng,1 S. Webber,1 A. Zeevi,1 E. Schuetz,2 J. Zhang,2 P. Bowman,1 J. Lamba,2 G.J. Burckart,1 1Pharmacy, Pediatrics, and Pathology, University of Pittsburgh, Pittsburgh, PA; 2Pharmacology, St. Jude Children’s Research Hospital, Memphis, TN Background: Pharmacogenomic predictors of drug response include both drug metabolism-disposition factors and drug targets. Information on statistical approaches to analyzing clinical data sets in relation to genetic polymorphisms is limited. Objective: To evaluate whether logistic regression could detect the pharmacogenomic predictors of outcome in a large data set in a transplant patient population. Methods: 77 pediatric heart transplant (HTx) patients were studied. Logistic regression analysis was used to identify the predictors using SPSS. Patients were followed for at least one year post HTx as outpatients, and weaned from corticosteroids if clinically appropriate. The dependent variable was the presence or absence of steroid therapy at one year post HTx. The independent variables were MDR1 exon26, CYP4503A5 and cytokine polymorphisms, tacrolimus blood level/dose, and rejection status based on heart biopsies. Results: Using logistic regression analysis, MDR1 exon26 (p⫽0.017), rejection status (p⫽0.046), transforming growth factor-beta (p⫽0.058) and interferon-gamma (p⫽0.077) were independently associated with steroid weaning. This confirmed the importance of MDR1 exon26; 12 of 18 (67%) patients in the CC group were still on prednisone, whereas only 18 of 47 (38%) of the CT/TT group were still receiving prednisone (p⫽0.04, Chi-square). Conclusions: This study confirms the utility of logistic regression analysis in the treatment of large data sets from complex patient populations. The major predictor of steroid weaning, the MDR1 exon26 genotype, was clearly demonstrated to be associated with the primary outcome measure while minor predictors were identified for future studies. This approach identifies pharmacogenomic factors which can be (1) studied more extensively in larger data sets, and (2) used in prospective analyses of the ability to individualize therapy based upon these factors. 210 EVEROLIMUS IS ASSOCIATED WITH A REDUCED INCIDENCE OF CMV INFECTION IN HEART TRANSPLANTATION