Improved survival induced by long term statin therapy following cardiac transplantation correlates with lipid lowering effect

The Journal of Heart and Lung Transplantation Volume 21, Number 1

Abstracts

increased NLC development. NLC prevalence reached 30% 13.3 years after Tx. Freedom from NLC Post-Tx; Acturial%(No at Risk) Year Regimen

1 2 3 4

0

3

6

9

12

100% (209) 100% (239) 100% (387) 100% (190)

100% (90) 97% (170) 94% (252) 96% (105)

85% (62) 89% (112) 87% (200) 5 yrs 94% (26)

79% (37) 78% (74) 82% (107)

67% (26) 73% (57) 79% (23) P ⫽ NS

177 PRE-OPERATIVE PULMONARY VASCULAR HEMODYNAMICS: RELATION TO SERIAL CLINICAL AND HEMODYNAMIC OUTCOMES UP TO 1 YEAR POST CARDIAC TRANSPLANTATION M. Rockx, P.W. Pflugfelder, W.J. Kostuk, 1Division of Cardiology, LHSC University Campus, London, Ontario, Canada; 2Division of Cardiology, LHSC University Campus, London, Ontario, Canada; 3Division of Cardiology, LHSC University Campus, London, Ontario, Canada Severe pre-operative pulmonary hypertension has been associated with sub-optimal outcomes following heart transplantation. In this retrospective review, serial clinical and hemodynamic outcomes were evaluated in a consecutive series of 442 cardiac transplants performed between 1981 and 2001. We examined PVR (⬍2, 2-5, ⬎⫽5), TPG (⬍10, 10-15, ⬎⫽15) and PA sys (⬍50, 50-70, and ⬎⫽70 mmHg) pre, 1 week, 3 months, and 1 year post transplantation. Increasing PVR and PA sys were similarly associated with higher mortality post transplantation, whereas TPG was not. *p⬍0.05 vs PVR ⬍5. Regardless of baseline pre-operative PVR, TPG, or PA sys, right heart hemodynamics were not significantly different between groups as early as 1 week post transplantation and continued to improve to 1 year. *p⬍0.05 vs PVR ⬍2. PVR ⬍2 PVR 2–5 PVR ⬎⫽5 TPG ⬍10 TPG 10–15 TPG ⬎⫽15

30 day

60 day

90 day

10.4 12.7 20.0* 13.4 11.3 13.6

14.2 17.3 25.0* 17.9 17.3 15.2

15.7 18.2 27.5* 19.4 18.0 16.7

Regardless of baseline pre-operative PVR, TPG, or PA sys, right heart hemodynamics were not significantly different between groups as early as 1 week post transplantation and continued to improve to 1 year. *p ⬍ 0.05 vs PVR ⬍ 2. Pre <2

Pre 2–5

Pre >ⴝ5

1 wk <2 1 wk 2–5 1 wk >ⴝ5 1 yr <2

R 11 ⫾ 7 12 ⫾ 6 9⫾6 9⫾6 9⫾5 4⫾3 A P 24 ⫾ 10 28 ⫾ 9 28 ⫾ 8 16 ⫾ 7 16 ⫾ 6 16 ⫾ 7 W P m 30 ⫾ 10 40 ⫾ 9* 46 ⫾ 10* 24 ⫾ 7 25 ⫾ 7 28 ⫾ 8 P A C 4.3 ⫾ 1.6 3.4 ⫾ 1.0* 2.8 ⫾ 0.7* 5.5 ⫾ 1.4 5.2 ⫾ 1.4 5.2 ⫾ 1.3 O

1 yr 2–5

1 yr >ⴝ5

5⫾3

5⫾2

11 ⫾ 4

12 ⫾ 5

12 ⫾ 6

19 ⫾ 5

20 ⫾ 6

21 ⫾ 6

6.2 ⫾ 1.4 6.1 ⫾ 1.4 5.8 ⫾ 1.0

In summary, TPG is a poor predictor of mortality post transplantation, whereas elevated PVR and PA sys present an increased but not universal risk of mortality. Even those with elevated PVR and PA sys are likely to have a rapid and sustained normalization of right heart hemodynamics. Selected patients with high PVR or elevated PA sys should not be excluded from consideration of transplantation.

119

178 PULMONARY HYPERTENSION BEFORE HEART TRANSPLANTATION IS ASSOCIATED WITH EARLY POSTTRANSPLANT PULMONARY HYPERTENSION BUT NOT WITH MORTALITY P.P. Chang,1 J.C. Longenecker,2 N. Wang,2 J.V. Conte,3 K.L. Baughman,1 J.M. Hare,1 E.K. Kasper,1 1Cardiology, Johns Hopkins University, Baltimore, MD; 2General Internal Medicine, Johns Hopkins University, Baltimore, MD; 3Cardiac Surgery, Johns Hopkins University, Baltimore, MD Pulmonary hypertension (PHTN) is common in severe heart failure. We tested whether PHTN before heart transplantation (tx) contributes to post-tx PHTN, re-transplantation, and mortality in 142 patients followed for 15.1 years with 3207 right heart catheterizations (cath). PHTN was defined as pulmonary vascular resistance (PVR) ⱖ2.5 Wood units. Post-tx PHTN was specified as occuring at 1, 3, and 6 months post-tx, anytime post-tx, and at last cath. Cellular rejection was defined as ISHLT grade ⱖ3A on biopsy, at similar specified time intervals as post-tx PHTN. 69 (40.8%) patients had pre-tx PHTN. Patients with pre-tx PHTN were more often nonwhite (15.9% vs 6.0%, p⬍0.05); other baseline characteristics were similar. During median follow-up of 4.7 years, 48 (69.6%) with pre-tx PHTN developed PHTN post-tx. After adjusting for race, donor age, heart size match, ischemic time, length of hospital stay post-tx, and secular trend, those with pre-tx PHTN had a higher risk of developing PHTN in the early follow-up period, e.g., at 3 months post-tx (n⫽24 [21.1%], relative hazards [RH] 3.05, 95% CI 1.11-8.39), and also had more episodes of post-tx PHTN (3.4⫾4.9) than those without (1.9⫾3.1, p⬍0.05). Alternatively, pre-tx PHTN was not related to post-tx PHTN at 6 months or at last cath. Those with pre-tx PHTN had more episodes of cellular rejection (4.0⫾3.8) vs those without (2.9⫾2.8, p⬍0.05), but pre-tx PHTN was not related to cellular rejection at any time point. Pre-tx PHTN was not associated with death (RH 1.80, 95% CI 0.86-3.78), re-tx (RH 0.40, 95% CI 0.03-3.09), or the two combined endpoints (RH 1.66, 95% CI 0.90-3.09), adjusting for gender, race, length of hospital stay, age at tx, heart size match, ischemic time, secular trend, cellular rejection and post-tx PHTN at anytime. In this cohort, pre-tx PHTN predicts early and more episodes of post-tx PHTN, but not mortality or re-tx. Results of this study suggests frequent monitoring of hemodynamics and rejection in patients with pre-tx PHTN. 179 IMPROVED SURVIVAL INDUCED BY LONG TERM STATIN THERAPY FOLLOWING CARDIAC TRANSPLANTATION CORRELATES WITH LIPID LOWERING EFFECT B. Orourke, M. Barbir, N. Banner, M. Yacoub, Cardiology and Transplant Medicine, Royal Brompton and Harefield NHS Trust, London, United Kingdom Statin therapy commenced immediately after cardiac transplantation reduces the incidence of allograft vasculopathy and improves survival. The immunomodulatory effects of statins have been well described and appear to be responsible for the early clinical benefits observed. However the long term impact and safety of lipid lowering therapy in this population is unknown. Hence we performed a retrospective study of patients receiving statin therapy over a ten year period at our institute.

120

Abstracts

The Journal of Heart and Lung Transplantation January 2002

Methods and Results: 249 cardiac transplant recipients(41 female) between 1989 and 1999 receiving statin therapy in combination with cyclosporin A were assessed from case records for lipid lowering effect, adverse events and survival. Four statins were used simvastatin(n⫽150), pravastatin(49), fluvastatin(40), atorvastatin(10). Mean treatment period(months); simvastatin 115.2, pravastatin 96.1, fluvastatin 59.9, atorvastatin 16.0. Percentage reduction in low density lipoprotein (at mean dose) was as follows; simvastatin(12.4mg) 30.3%, pravastatin(29.3mg) 29.4%, fluvastatin(40mg) 28.9%, atorvastatin(10mg) 32.1%. Adverse events; elevated creatinine kinase and myalgia: simvastatin 18%, pravastatin 9%, fluvastatin 0%, atrovastatin 0%. Elevated hepatic transaminases; simvastatin 6%, pravastatin 0%, fluvastatin 0%, atorvastatin 0%. Overall using the Cox proportional hazards model, percentage reduction in total cholesterol (p⫽0.006) and LDL cholesterol (p⫽0.01) correlated most strongly with improved survival. However there was no significant evidence for a difference in survival time between the four statins used (p⫽0.29). Conclusion: Significant reductions in lipids can be achieved safely using long term statin therapy following cardiac transplantation. Previous evidence has suggested that the benefits of these drugs in this population are immune mediated independent of lipid lowering effect. The results of this study suggest that the lipid lowering effect of these drugs is also important particularly in the long term. 180 RENIN-ANGIOTENSIN-ALDOSTERONE-SYSTEM DIRECTED ANTIHYPERTENSIVE THERAPY ACHIEVES LOWER B-TYPE NATRIURETIC PEPTIDE LEVELS COMPARED WITH CALCIUM CHANNEL BLOCKADE IN HEART TRANSPLANTATION M.H. Park, P.A. Uber, R.L. Scott, L.E. Bourgeois, M.R. Mehra, Ochsner Clinic Foundation, New Orleans, LA Background. The optimal antihypertensive regimen after heart transplantation remains elusive and poorly defined. Whether therapy targeting the renin-antiotensin-aldosterone system (RAAS) evokes benefits beyond blood pressure (BP) lowering in heart transplantation has not been previously determined. We hypothesized that RAAS directed therapy compared with calcium channel blockade (CCB) would be more likely to decrease b-type natriuretic peptide (BNP) levels, a sensitive and specific marker of ventricular overload, at similar blood pressure(BP) control. Methods. In 30 consecutive stable heart transplant recipients, we compared BNP levels between patients receiving a primary RAAS targeted therapy (n⫽14) for hypertension versus CCB therapy (n⫽16). All patients (80% men, 87% whites, age 61⫾4years, tacrolimus, mycophenolate and steroid immunosuppression) achieved BP control to a systolic and diastolic BP⬍140/90 mmHg with stable allograft function (Ejection Fraction 63⫾5%) without ongoing rejection). Results. In the RAAS directed treatment group, 71% received angiotensin receptor blockers while 29% were on angiotensin converting enzyme inhibitors. All patients in the CCB group recieved amlodipine. Findings are depicted in the table below. Systolic BP RAAS Group CCB Group p value

129 ⫾ 11 130 ⫾ 9 0.7

Diastolic BP 84 ⫾ 8 84 ⫾ 6 0.9

BNP (pg/dl) 89 ⫾ 78 174 ⫾ 136 0.05

Regression analysis of systolic and diastolic blood pressure with BNPlevels failed to demonstrate any significant correlation. Similarly no significant correlations of renal function and BNP levels were noted in this cohort. Inferences. Despite similar levels of blood pressure control achieved with CCB’s, RAAS directed antihypertensive therapy is associated with lower BNP levels, a sensitive and specific marker of ventricular wall stress. Thus, we suggest that RAAS directed therapy evokes benefits on cardiac allograft adaptation beyond those achieved by blood pressure lowering alone. 181 TACROLIMUS/MYCOPHENOLATE MOFETIL VS CYCLOSPORINE/MYCOPHENOLATE MOFETIL: IMPACT ON INFECTIONS FOLLOWING CARDIAC TRANSPLANTATION J. Groetzner, B. Meiser, J. Schirmer, S. Schenk, M. Muller, F. ¨ berfuhr, B. Reichart, Klinikum Reisch, M. Oberhoffer, F. Kur, P. U Grosshadern, University Hospital, Munich, Germany Background: New combinations of immunosuppressive agents led to a decrease of acute rejection episodes (ARE) after HTx. They might be associated with an increased risk of infections. Therefore we compared the incidence of infections in HTxpatients treated with either a Tacrolimus- (Tac) - or a Cyclosporine- (CsA) based immunosuppression. Methods: In a prospective, randomized clinical trial, 61 HTx patients (n⫽30/31) were included during 1999 and 2001. Immunosuppression consisted of CsA, Mycophenolatmofetil (MMF) and Corticosteroids (Cort) or Tac, MMF and Cort. Cort were stopped as early as 6 month po. Endpoints were incidence of infections and ARE. Infections were defined as positive cultures or laboratory values with the need of antibiotic treatment. Results: Demographic data as well as primary diagnosis and perioperative data were comparable between both groups. Comparison of the infection incidence revealed a trend towards an increase in CsA-patients (0.31 inf./100pat.days vs. 0.27 (Tac); p⫽n.s.). Distribution of the bacterial, viral and fungal infections were similar in both groups: (CsA vs Tac) Bacterial: 45% vs 50%; Viral:27% vs. 29%; Fungal: 28% vs 21%, p⫽n.s.). Incidence of ARE/100 pat.days was significantly lower in the Tac/MMF group when compared to the CsA/MMF group (0.09 and 0.3; p⬍0.003). Nineteen infections in the CsA and 4 in the Tac group occured within 3 weeks after ARE treatment. ( p⬍0.05 ). Especially the incidence of fungal and viral infections following ARE was significantly higher in CsA treated patients (fungal: 7 vs 0; p⫽0.03; Viral: 7 vs 2; p⫽0.05; Bacterial: 6 vs 2; p⫽n.s.). Overall Survival was 90% (CsA) vs. 96% (Tac), the percentage with lethal infections (aspergillus-pneumonia)was comparable (6,7% (CsA) vs. 3,3% (Tac) p⫽n.s.). Conclusion: The immunosuppressive combination of Tac/MMF resulted in a trend to less infections after HTx than CsA/MMF. This tendency was in many cases contributed to augmented immunosuppression during rejection treatment. Since there is a significantly higher incidence of ARE in CsA-treated patients, Tac/MMF proved to be the combination with the favorable safety profile. 182 DEVELOPMENT OF A NOVEL PRECLINICAL PIG-TONON-HUMAN PRIMATE MODEL OF XENOGENEIC ORTHOTOPIC LUNG TRANSPLANTATION