Statins and the Risk of Cancer after Heart Transplantation Georg Marcus FrГ¶hlich, Kaspar Rufibach, Frank Enseleit, Mathias Wolfrum, Michelle von Babo, Michelle Frank, Reto Berli, Mathias Hermann, Johannes Holzmeister, Georg Noll, Thomas F. LГјscher and Frank Ruschitzka Circulation. published online July 3, 2012; Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright В© 2012 American Heart Association, Inc. All rights reserved. Print ISSN: 0009-7322. Online ISSN: 1524-4539 The online version of this article, along with updated information and services, is located on the World Wide Web at: http://circ.ahajournals.org/content/early/2012/06/28/CIRCULATIONAHA.111.081059 Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Circulation can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for which permission is being requested is located, click Request Permissions in the middle column of the Web page under Services. Further information about this process is available in the Permissions and Rights Question and Answer document. Reprints: Information about reprints can be found online at: http://www.lww.com/reprints Subscriptions: Information about subscribing to Circulation is online at: http://circ.ahajournals.org//subscriptions/ Downloaded from http://circ.ahajournals.org/ by guest on June 9, 2014 DOI: 10.1161/CIRCULATIONAHA.111.081059 Statins and the Risk of Cancer after Heart Transplantation Running title: FrГ¶hlich et al.; Statins and cancer after heart transplantation Georg Marcus FrГ¶hlich, MD1; Kaspar Rufibach, PhD2; Frank Enseleit, MD1; Mathias Wolfrum, MD1; Michelle von Babo, BSc1; Michelle Frank, MD1; Reto Berli, MD1; Mathias Hermann, MD1; Johannes Holzmeister, MD1; Georg Noll, MD1; Thomas F. LГјscher, MD1; Frank Ruschitzka, MD1 1 Cardiovascular Ca rdi rd diova iova v scul ulaar ul ar Center, Center, Cardiology, Univers University sit ity Hospital Zuric Zurich; icch; h 2Di Division Div vision of Biostatistics, Institut Institute utee for for Social S ciial and So and Preventive Pre P reve re vent ve n iv nt ivee Medicine, Meedi dici c ne ci ne,, University Univ iv ver ersi sity si ty of of Zurich, Zu uri r ch h, Zurich, Zuri Zu rich ch,, Sw ch Swit Switzerland itze zerl ze r an rl andd Correspondence: Corr rrespo p nd po nden ence: Georg Geor Ge o g Marcus Marc rcus us FrГ¶hlich, FrГ¶ Г¶hllic i h, MD MD Cardiovascular Center Cardiology Heart Failure/Transplantation Clinic University Hospital Zurich RГ¤mistrasse 100 CH-8091 Zurich, Switzerland Tel: +41 44 255 1111 Fax: +41 44 255 4401 E-mail: [email protected] Journal Subject Codes: [11] Other heart failure; [112] Lipids; [27] Other Treatment 1 Downloaded from http://circ.ahajournals.org/ by guest on June 9, 2014 DOI: 10.1161/CIRCULATIONAHA.111.081059 Abstract: Background - While newer immunosuppressive agents, like mTOR inhibitors, have lowered the occurrence of malignancies after transplantation, cancer is still the leading cause of death late after heart transplantation. Statins may impact on clinical outcomes beyond their lipid-lowering effects. The aim of the present study was to delineate whether statin therapy impacts on cancer risk and total mortality after heart transplantation. Methods and Results - 255 patients who underwent heart transplantation at the University Hospital Zurich between 1985 and 2007 and survived the first year were included. The primary outcome measure was the occurrence of any malignancy, the secondary endpoint overall survival. urvival. During follow-up, a malignancy was diagnosed in 108 patients (42%). The The cumulative cu umu mula lati la tive v incidence ncidence of tumors 8 years after transplantation was reduced in patients receiving a statin (34% vs.13%, vs s.113% 3%, 95% 95% CII 0.25-0.43 00.2 .25-0.43 vs. 0.07-0.18, p<0.003). p<0.0003). Statin use was waas associated asso sooci ciat a ed with improved cancer-free and overall survival Cox-regression model ca ancer-free ncc an nd ov over ral a l su surv rviv ivaal iv al ((both both bo t pp<0.0001). th <0.0 000 01). A Co ox-re x-regr grres esssion m o el aanalyzing od naly na lyzi zing zi ngg tthe h ttime he ime tto im o tumor umo morr fo fformation rm mat atio ionn with with orr without w th wi houut statin stat st a in at n therapy, tthe hera he rapy, ra y, adjusted aaddjuuste teed for for age, age, male mal alee gender, geend ndeer, er ty type pe ooff cardiomyopathy cardiomyop patthy and and immunosuppressive iimm m un mm unos o up os uppr p es pr essiive v therapy tthe hera he rapy ra py (including (inc n lu udi d ng switch swi witc t h too mTOR mTO m TOR TO R inhibitors inhi in hibi hi b to bi t rs or tacrolimus) demonstrates a superior survival in the statin group. Statins reduced the hazard of occurrence of any malignancy by 67% (HR 0.33, 95% CI 0.21-0.51, p<0.0001). Conclusions - Although it is not possible to adjust for all potential confounders due to the very long follow-up period, this registry suggests, that statin use is associated with improved cancerfree and overall survival after cardiac transplantation. These data will have to be confirmed in a prospective trial. Key words: cholesterol; heart transplantation; statins; transplantation; malignancy 2 Downloaded from http://circ.ahajournals.org/ by guest on June 9, 2014 DOI: 10.1161/CIRCULATIONAHA.111.081059 Introduction Newer immunosuppressive regimens like mTOR inhibitors or tacrolimus have not only steadily reduced the incidence of acute rejection, but also of post-transplant malignancy1-3. However, malignancy still is an important cause of long-term mortality in transplant recipients4. The incidence of malignancy has been estimated at 20% after 10 years of chronic immunosuppression5, and the relative risk may increase 100-fold for specific cancers in comparison to the general population6. Heart transplant patients are at particular risk of developing posttransplant malignancies that is increased up to four-fold compared to renal transplant recipients.6-11 Indeed, cancer is now a leading cause of death late after heart transplantation ransplantation12. Importantly, HMG-CoA-reductase-inhibitors (statins) initiated after heart transplantation exert ex xerrt be bene beneficial neefi fici cial eeffects ci ffects on the incidence of cardiac ff cardia iacc aallograft ia llograft reject rejection, cttio i n,, tr transplant tra an ansplant vasculopathy 13,14 14 and an nd survival rat rates. tes. es 13, IIntriguingly, ntri ntri rigu guin gu ingl in gly, y, iin n no non-transplant on-trran nspllannt ppatients, attie ienntss, s, sst statin tatin intake inttakke in ke is is associated asso as soociiat a ed e with with itth a 1 decreased decr de crea cr ease ea s d risk se risk of of malignancies maliignnancie mali ies such ie such aass ly lymphoma ymp mpho ho oma155, brea bbreast rea east st1166,o ,ovarian ,ova vaariian17 , ccolorectal olo ore r ct c all1188, lung lu ungg and aan nd nd 19,20 20 pancreatic can an nce cerr19 . Wh W While ilee el il eelevated evat ev a ed at e pplasma lasm la smaa ch sm cholesterol hol o es este t ro te ol le leve levels v ls hhave ve av ve be been en aassociated ssoc ss ocia oc iate ia tedd with the te cancer development of skin, colon or prostate cancer21-24, it is matter of a still ongoing debate whether the potential benefit of statins in cancer may be explained by its cholesterol-lowering or potential pleiotropic, particularly immunomodulatory effects.25,26 To the best of our knowledge, up to date no data exist on the impact of statin use or cholesterol levels on cancer risk in immunosuppressed patients. Hence, the aim of this study was to evaluate the influence of statin therapy and cholesterol levels beyond the role of immunosuppression on the development of malignancies and total mortality. 3 Downloaded from http://circ.ahajournals.org/ by guest on June 9, 2014 DOI: 10.1161/CIRCULATIONAHA.111.081059 Methods Study design and patient sample We evaluated all patients 18 years of age or older, who underwent heart transplantation at the University Hospital Zurich between 1985 and 2007 and survived the first year after transplantation. Statin therapy was initiated usually three to twelve months after transplantation in patients transplanted after year 1995. Statin therapy was recorded on a daily basis from heart transplantation until the occurrence of malignancy or the end of the follow-up period. Follow-up was performed until December 2010. All patients who received a statin were assigned to the statin group. Further, detailed information inhibitors nformation of immunosuppressive therapy including switch to mTOR inhibitor rs orr ttacrolimus, accro roli limu li m s, mu s lipid ipid status as well as episodes of rejections were recorded. Rejection was defined according to International Society Transplantation (ISHLT) criteria, nteern rnat atio at iona io nall So na oci cieety ety for Heart and Lung Transp pla lanntation (ISHLT T) crit iter eriia, er ia based on findings in the he re regular en endomyocardial ndo domy myoc my ocaardi dial di al bbiopsies iops io psie i s (> ie > IISHLT SH HLT T IB B - occ occurred cccurre urreed in nn=205, =205,, 881% =205 1% % - an andd IS ISHL ISHLT H T > II HL occurred separately) oc ccu curr rred rr e in ed in n=167, n=16 n= 16 67,, 666% 6% - aaree sshown hown ho wn ssep epar ep arat ar atelly) at y 2277. On Only nly y bbi biopsy iops iops psyy pr prov proven oven ov en n rejections rej ejec ecti ec tiion o s > 1 month mont mo nthh after the previous prev vio ious u bbiopsy us i ps io p y we were re ccounted ount ou nted nt ed d aass a de nnovo ovoo rrejection. ov e ec ej ecti tion ti on.. on Immunosuppressive therapy followed a standardized protocol in all patients and was recorded after 12 months, when levels of immunosuppressive drugs were in a steady state. Presence of malignancy was ruled out prior to transplantation in all patients according to the guidelines of the ISHLT.27-29 Study endpoints The primary outcome measure was the time from HTX to the occurrence of any malignancy, defined as the detection of any malignant tumor. For this endpoint, the competing event “death from non-malignant cause” was considered. 4 Downloaded from http://circ.ahajournals.org/ by guest on June 9, 2014 DOI: 10.1161/CIRCULATIONAHA.111.081059 Secondary endpoints were overall survival and time to tumor occurrence for which we additionally distinguished between skin vs. non-skin malignancies. “Non-skin” malignancies included lymphoma, multiple myeloma, tumors of bladder, lung, gastrointestinal system, kidneys and of unknown origin. Further, we investigated whether high cholesterol is an independent risk factor for the occurrence of a malignancy or of the competing endpoint of death from a nonmalignant cause. Study groups The outcome of patients receiving statin therapy was compared to patients without statins. Each day on statin treatment was recorded and patients were divided into subgroups who received statins tatins for more than 50% of the follow-up compared to with patients with less than th han n 50% 50% of of follow-up. Patients were divided into a low-dose group (equivalent simvastatin dose of 10-30 mg) high-dose simvastatin mg). mg g) an andd a hi hig gh-d dose ose group (equivalent simvastat atin at i dose of 40-80 in 0m mg) g).30 T The decision to put patients pati ien e ts on a “h “high-dose” hig i h-do dose do see” st stat statin atin at in tthe therapy herrap he rapy w was ass bbased asedd oon n ccholesterol holeestter hole erool ol vvalues alue al uees > 5.5 5.5 mm mmol/l mol ol/l /l ((n=24, n=24 n= 24, 4 16% 16 6% of patients pattie ient ntss on statin). ssta taati tinn). n). Furthermore, Furthe heerm rmor ore, or e, ppat patients attient ntss we nt were ere aassigned s ig ss igne nedd to ne o ttwo wo ggro groups r up ro upss ba base based sedd onn their se the heir ir mean mea m e n fa ea fast fasting stin st ingg total in cholesterol (TC) of all cholesterol measurements after three months after HTX, i.e. in a „highcholesterol group“ (TC В• 5.5 mmol/l) and a „low-cholesterol group“ (TC < 5.5 mmol/l),31 as lipid levels change due to immunosuppressive therapy after HTX.32 Statistical analyses Statistical analysis was performed using “R” Software and Stata 11.2 (StataCorp, College Station, TX).33 The survival analysis was performed using the R-package survival34 Cumulative incidence curves are computed using the package “cmprsk”.34 Nominal variables are presented as absolute (n) and relative frequency (%). To assess differences in nominal variables between 5 Downloaded from http://circ.ahajournals.org/ by guest on June 9, 2014 DOI: 10.1161/CIRCULATIONAHA.111.081059 groups we used either Chi2 or Fisher's exact test, whichever was appropriate. Continuous variables are presented as median and interquartile range (25-75 percentile) within brackets. To assess differences between groups, the Mann-Whitney U-test was used. To assess time-to-event endpoints with competing events, we computed cumulative incidence curves and provide estimates of the cumulative incidences at 8, 10, and 12 years including 95% confidence intervals. Cumulative incidence curves were compared between groups according to the method of Gray.35 For the primary outcome measure “freedom from malignancy”, the competing events “occurrence of skin malignancy”, “non-skin malignancy”, “death from non-malignant cause”, and “censored” (denoted “event-free survival”) were distinguished. h ccovariates he ovar ov aria ar iate ia tes Cox regression models were used to analyze the independent influence off the “statin-group” on malignancy formation, where we adjusted these models for age, sex, un nde derl rlyi rl ying yi ng g hhe eartt ddis i ease, conventional immunos is sup u pression and cchange h ng ha ge to to mTOR inhibitors or underlying heart disease, immunosuppression acrrolimus (mT mTOR OR aand n ttacrolimus nd accro roli limu li muss as as ttime-dependent im me-ddeppenddent co co-v -vaariiate tess). tacrolimus (mTOR co-variates). ass sses esss whether whettheer the whet the relative reela lati tivve ti ve risk rissk reduction reduuct re c ion off tthe he statin sstaati t n therapy th her eraapy py iiss in ind depe depe pend nden nd en nt of o To assess independent leeve vels ls and and n of of interactions in nte tera r ct ctio ions io ns between bbet etwe et ween we en statin ssta tati ta tinn therapy ti t errapy and th and cholesterol ccho hole ho leest ster erol er ol values, vval alue al ues, ue s, a Cox Cox cholesterol levels regression model with cholesterol (cholesterol as nominal co-variate В•5.5 mmol/l vs. <5.5 mmol/l ) and the “statin-groups” was determined. Kaplan-Meier estimates and log-rank tests for overall survival and median follow-up were computed using inverted Kaplan-Meier estimate. Confidence intervals for median time to event were computed using the method by Brookmeyer and Crowley.36 A significance level of Д® = 0.05 was adopted throughout the study and all confidence intervals are computed using a confidence level of 95%. Ethics committee approval The study was approved by the ethics committee of the University of Zurich, Zurich Switzerland. 6 Downloaded from http://circ.ahajournals.org/ by guest on June 9, 2014 DOI: 10.1161/CIRCULATIONAHA.111.081059 Results Patient characteristics All 255 patients who underwent heart transplantation at the University Hospital Zurich between 1985 and 2007 and survived the first year were included (Table 1). The median follow-up for event-free survival from cancer was 12.6 years (25th-75th percentile 11.0 – 14.0 years, Table 1). During follow-up 94 patients (37%) died, of whom 29 patients (11%) died due to a malignancy. The groups did not differ with regard to age, gender, mean cholesterol values, rejections per patient per year and CMV risk (Table 2). Cumulative incidences of occurrence of neoplasia were 21% (95% CI 0.16 – 0.26%) at 0.25 25 – 0.36%) 0 36 0. 36%) %) eight years follow-up, 27% (95% CI 0.21 – 0.32%) at ten years and 30% (95% CII 0.25 at twelve years. Cumulative incidences of skin malignancies were 11% (95% CI 0.07 – 0.15%) aat eiigh ht years year ye arrs follow-up, follow fo ow w-up, -u 15% (95% CI 0.11 – 0.20%) 0.20 0%) %) at ten years and and n 17% 7% (95% CI 0.12 – 0.21%) eight welve years. yearrs. s Cu C umulat umu atiive ive in inci cide deence nces ooff th he comp mpetin mp in ng en ndpoi oint nt ““death deaath fr de rom nnon-malignant on-m on - al -m a ig gnaantt att tw twelve Cumulative incidences the competing endpoint from caaus use” e” w erre 12% 12% (9 (955 % CI 00.08 .088 – 0. .0 00.16%) 16 6%) aatt ei eigh ghtt yea gh yyears ears ars fo fol llow llow ow-u -u up, p 113% 3% % ((95% 955% CII 00.09 .09 09 – 0. 0.1 17%) %) cause” were eight follow-up, 0.17%) nd 116% 6% ((95 95 5%C .122 – 0. .1 0.21 21%) 21 %) aatt tw twel elve el ve yyears. ears ea rs. rs at ten years aand CII 00.12 0.21%) twelve Impact of statin therapy on malignancy formation and mortality Of the 151 patients on statin therapy, 83 patients (57%) received low-dose (equivalent to simvastatin 10-30 mg) and 61 (42%) a high dose statin therapy (equivalent to 40-80 mg simvastatin). In seven patients detailed information on statin dose was lacking. Statin intake was recorded on a daily basis in the statin study population: Patients were on statin therapy for a median of 64% (25th-75th percentile: 42 – 93%) of the follow-up time (time to occurrence of cancer). During follow-up, a malignancy was diagnosed in 108 patients (42%). Patients on statin therapy were more likely to survive without occurrence of malignancies (p < 0.003, Figure 1). 7 Downloaded from http://circ.ahajournals.org/ by guest on June 9, 2014 DOI: 10.1161/CIRCULATIONAHA.111.081059 Patients in the statin group were at a lower risk of malignancy formation compared to the non-statin group (13% vs. 34%, CI 0.07 – 0.18 vs. 0.25 – 0.43 ) at eight years after transplantation, (18% vs. 39%, CI 0.12 – 0.24 vs. 0.30 – 0.49) 10 years after transplantation and (22% vs. 42% , CI 0.15 – 0.28 vs. 0.33 – 0.52; p<0.003. Figure 1) 12 years of follow-up. “Non-malignant cause of death” is a competing endpoint: statin use was associated with a reduction of risk to die from a non-malignant cause compared to the non-statin group, (7% vs. 19%, CI 0.03 – 0.11 vs. 0.12 – 0.27) eight years after transplantation, (9% vs. 19%, CI 0.04 – 0.13 vs. 0.12 – 0.27) 10 years after transplantation and (11% vs. 24%, CI 0.06 – 0.16 vs. 0.16 – 0.32; p = 0.02; Figure 1) twelve years of follow-up. Similarly, statin use was associated with a reduced risk of developing non non-skin n-sk skkin malignancies (4% vs. 18%, CI 0.01 – 0.07 vs. CI 0.11 – 0.26) eight years after f transplantation, 10 years after transplantation 0.12 year ye arss af ar aft ter tr ter tra ansp sppla lant n ation (5% vs. 20%, CI 0.02 2 – 00.09 .09 vs. CI 0.1 12 – 0. 00.28) 28 and twelve years of 28) follow-up while was folllow-up (7% % vvs. s. 22% 222% vs., vs , CI 0.03 0.0 0 03 – 0.11 0.111 vs. 0. vs. CI 0.14 0. – 00.30; .330; pp=0.04; =0.04; =0.0 4; Figure Figu Fi gure re 22), ), w hile hi le tthere here he ree w as no difference ddif iffe if fere fe renc ncee for nc for occurrence occu occu urr rren e ce of en of skin skin malignancies mal alig igna ig nanc na nccie i s between be wee betw eenn the th he statin sttattin and and the thee non-statin nnon o -s on -sta tati ta tinn grou ggroup rou up (p=0.2, p=0.2, Figure Figu ure 22). ).. Patients receiving statins for more than 50% of the follow-up time had a lower risk of malignancy occurrence compared to patients who received a statin for less than 50% of followup time (p=0.02). This benefit persisted at eight years (16% vs. 25%; CI 0.08 – 0.23 vs. 0.18 – 0.32), ten years (21% vs. 31%; CI 0.13 – 0.29 vs. 0.23 – 0.38) and twelve years of follow-up (25% vs. 34%, CI 0.16 – 0.34 vs. 0.26 – 0.41; Figure 3). Moreover, patients on statin treatment В• 50% of the follow-up time were less likely to die from a non-malignant cause auf death compared to patients receiving statins less than 50% of the follow-up time (p-value: 0.007; Figure 3). Importantly, this benefit persisted eight years (7% vs. 8 Downloaded from http://circ.ahajournals.org/ by guest on June 9, 2014 DOI: 10.1161/CIRCULATIONAHA.111.081059 15%; CI 0.02 – 0.13 vs. 0.09 – 0.20), 10 years (7% vs. 17%, CI 0.02 – 0.13 vs. 0.11 – 0.22) and 12 years after transplantation (8% vs. 21%, CI 0.03 – 0.14 vs. 0.15 – 0.27). A Cox-regression model analyzing the time to tumor formation with or without statin therapy, adjusted for age, male gender, type of cardiomyopathy and immunosuppressive therapy demonstrates a lower hazard for tumor in the statin group. (Table 3). Overall survival was improved in patients on statin therapy vs. the control group (p<0.0001; Figure 4). Statin dose was not associated with malignancy occurrence (p=0.44). Impact of cholesterol levels on malignancy formation and mortality In 239 of 255 patients serial cholesterol measurements, obtained at least three months after HTX, were available (median number of 5.5 cholesterol values (min. 3 – max. 13). In a Cox-regression Co ox-re regr gres gr essi es sion model analyzing the event free survival in patients with or without statin therapy and cholesterol levels co-variates, statin eveels (В•5.5 ((В• В•5.5 5.5 mmol/l mmol mmol ol//l /l vs. <5.5. mmol/l) as co-varia iaates, the benefit of sta ati tinn therapy t erapy (p= 0.0009, HR th 0.43, was independent cholesterol 0.43 3, 95% CI 00.26-0.71) .266-0. .2 0 71) wa as in inde depe pend pe nd dennt off pplasma lasm ma cho hole ho lessteerol llevels evel elss (p p = 00.76, .76, .7 6, H HR R 11.09, .09 9, 995% 5% CII 0.26-1.92). therapy and values the 00.2266 1. 1.92 92)). 92 ). No No significant sign si gniffic gn ican antt interactions in nte tera racctio ra ctio ons between bbeetwe ween we en n sstatin tattin th ta ther erap apyy an ap nd cho ccholesterol holes olesste t ro roll va valu luees es oon n th he developmentt of tumors increased risk “nontum umor orrs were weere detected ddet etec et ecte ec teed (p=0.72). (p=0 (p =0 0.7 .72) 2 . But, 2) But,, there tthe heere was wass an an in incr crea cr ease ea sedd ri se isk ffor or “no n nmalignant cause of death” in the high cholesterol group (p=0.0003). In the high cholesterol group, patients on statin therapy had an improved survival as compared to those patients without statin (p=0.0003). Discussion We here demonstrate that statin use is associated with a substantial reduction of cancer risk and all-cause mortality in heart transplantation recipients. With a follow-up of up to 25 years it is not possible to adjust away all the differences in therapy and especially during the recent era when 9 Downloaded from http://circ.ahajournals.org/ by guest on June 9, 2014 DOI: 10.1161/CIRCULATIONAHA.111.081059 statins were used compared to the previous era in which there was more intense immunosuppression with agents more likely to cause malignancy. Over the last three decades the development of tumors in transplant recipients steadily decreased by the introduction of newer immunosuppressive drugs, like mTOR inhibitors or tacrolimus.3,12 However, while the one year survival rate improved dramatically since the early era of organ transplantation due to more targeted immunosuppression and optimized strategies to prevent severe acute organ rejections, overall long term survival did not further improve over the last 20 years12. Long-term outcome after cardiac transplantation is still limited by graft atherosclerosis and particularly by the risk of developing cancer, which remains a leading cause 6,9,11,12 9,11 ,11,12 11,12 of death after 15 years, modern immunosuppressive therapies notwithstanding.6,9 Hence, Henc He nce, nc e tthe e, observed 67% hazard reduction to develop cancer associated with the use of statins in the presen present study tud dy is of of pa part particular r iccul ular a clinical relevance. Importa Importantly, ant ntly y, the benefits ooff st statins tat atin ins were observed on top in off the the use of modern mode mo dern de n immunosuppressive iimm mm mun unos osup os uppr preess pr essive therapy thherapy y – mTOR mTO TOR TO R inhibitors, innhib nhib bittor ors, iin n pa par particular. rticul rti icular ar. ar These Thes Th esee findings es finndi fi ndings ingss are are r inn line l ne with li wiith w ith results resu re sult su lts from lt from m recent reccen nt case-control casee-c case - on ontr trol tr ol studies stu tu udiies e in in nonnonimmunosuppressed mmunosupp pppre ress s ed patients ss pat a ie i ntts indicating indi in dica di cati ca tiing n that tha hatt statin stat st a in at i use usee is aassociated ssoc ss ocia oc iaate tedd wi w with th a rred reduction e uc ed ucti tion ti on ooff the risk off colon18, lung19 and pancreatic cancer20. In addition, a potential for statins as adjuvant therapy has been suggested, as statins reduce proliferation and increase apoptosis in women with high grade breast cancer16. Similarly, statins induce apoptosis of ovarian cancer cells and synergize with doxorubicin17. Moreover, the reduction of cancer risk in heart transplant recipients receiving statins was paralleled by a substantial reduction of total mortality. This confirms and extends findings of previous studies of Kobashigawa et al. that pravastatin improves survival after heart transplantation particularly due to a reduction in graft atherosclerosis14. While the survival 10 Downloaded from http://circ.ahajournals.org/ by guest on June 9, 2014 DOI: 10.1161/CIRCULATIONAHA.111.081059 benefit associated with the use of statins had been subsequently been confirmed by other groups and other statins, data on cancer risk had not been reported37-39. Since the benefits of statins on mortality and cancer risk in the present study were independent of cholesterol lowering, potential mechanisms associated with the inhibition of the mevalonate HMG-Coenzyme A reductase pathway beyond cholesterol lowering alone should be considered. Indeed, statins downregulate the synthesis of dolichol, ubiquinol farnesol and geranylgeraniol40,41, all of which are associated with cell transformation42, cell proliferation43 and angiogenesis44. Moreover, statins induce apoptosis via activation of caspase and mitochondrial pathways45 and modulate cell migration by down-regulating chemokine secretion and receptor expression in a geranylgeranylation dependent mechanism.40,46,47 In addition, statins suppress several adhesion molec molecules eccul ules e iin n or orga organ gann ga tissue issue and leukocytes such as ICAM-1 or VCAM-148 regulate metalloproteinases and several cy yto oki kinnes nes that that a are ree permissive ppeermissive for tumor growth.49 A As inhibition off me m metalloproteinases taall llooproteinases might cytokines 50 prev prevent ven e t cell tra transformation rans nssfo orm mat atio ionn50 io aand nd sstatins taati tin ns may ns y rreduce eduuce uce ttumor umor um orr fformation orm or mation mat on ass we well ell aass graf ggraft raf aftt 51,52 51 52 rejection. eje ject cttio ion. n.51, Interestingly, Intere est stin in ngl gly, y, tthe he beneficial ben enef en e iccia ef iall effects e feect ef c s of st sstatins a in at inss in i the the present ppre r se re sennt study stud st udyy were ud were r not not only onl nlyy independent of the immunosuppressive therapy but also of statin dose and cholesterol levels. Even in the “high-cholesterol” subgroup (defined as a mean cholesterol value of more than 5.5 mmol/l), patients on statin therapy were at a lower risk of malignancy formation compared to patients without statin treatment. Is there a link between cholesterol levels and cancer development? In patients after solid organ transplantation, data on the relation of cholesterol and statins on clinical outcome are sparse. In the present study, no significant association of elevated cholesterol values and cancer risk was detected. However, cholesterol is a major component of 11 Downloaded from http://circ.ahajournals.org/ by guest on June 9, 2014 DOI: 10.1161/CIRCULATIONAHA.111.081059 the cell membrane and plays an important role in vesicular trafficking and cellular pathways. In line with this concept, Zhuang et al. could demonstrate a decreased apoptosis rate in cholesterol enriched prostate cancer cells53. Moreover, cholesterol levels influence the activity of metalloproteinases that are actively involved in tumor promotion54-56 and could represent another link between cholesterol and tumor growth. While an inverse association of cholesterol levels and cancer risk had been reported previously57-59 more recent evidence suggest that this observation may be due to reverse causation59. Therefore, a potential role of cholesterol in the development of malignancies remains still elusive. The role of newer immunosuppressive agents in malignancy formation Transplant-related malignancies arise from a complex interplay of immunologicc aand nd d nnonon-on mmunologic risk factors4. It still remains a matter of debate, however, whether the type of immunologic mmu munnosu nosuupp p ress sssiv ivee regimen, total dosage and du dura rattion of treatm men e t orr tth he degree of immunosuppressive duration treatment the immunosuppression, mmunosuppre mu ress sssio on, n aare ree rrel relevant elev el evaant ev an to de determining eteermiining can ccancer anceer er rrisk. iskk. P is Previous reevi viouus pu publications ub icaati ubli tion onns de demo demonstrated, mons mo nstr t ated tr at that hat the the risk ris riskk of of pposttransplant osstt ttra raansspl p an antt ma mali malignancies lign li gnan an nciies iis li link linked nkked dw with itth azathioprine, azat azat athi h opri hi opri rine n , bbut ne ut not not with wiith newer nneewer ewer agents ageent ns such uch as myco mycophenolate oph phen en nol olat atte mofetil mo ofe feti t l and and sirolimus. s ro si oli limu mus. mu s. 4 P Preliminary Pre reli re liimi m na nary ry llong-term ongon g teerm ddata gataa su at supp support ppor pp ortt th or the use of these newer agents, like mTOR inhibitors or tacrolimus, with potential antitumor properties and lower cancer risk in transplant recipients12. Limitations It has to be acknowledged that it is not possible to adjust away all the differences in therapy over a two decades follow-up and especially during the recent era when statins were more frequently used compared to the previous era in which more intense immunosuppression was more likely to cause malignancy. While retrospective analyses are subject to bias and confounding, randomized clinical trials addressing the role of statins in cancer in immunosuppressed patients are still 12 Downloaded from http://circ.ahajournals.org/ by guest on June 9, 2014 DOI: 10.1161/CIRCULATIONAHA.111.081059 lacking, which is mainly due to the long follow-up periods needed. Especially, the difference in azathioprine use between the study groups could be an important confounder. However, in a Cox regression model, azathioprine was not an independent risk factor for cancer in our study population. Only 18% of patients were switched to mTOR inhibitors or tacrolimus over time. Thus, cancer risk can be further reduced in the future with the use of newer immunosuppressive drugs. The sample size of the present study has to be weighed against the high event rate of tumor occurrence and the long follow-up period of up to 25 years with a median follow-up for overall survival of 14.4 years. Importantly, all patients included in the study underwent a rigid heart post-transplant follow-up schedule according to a standardized protocol in our he earrt transplantation ransplantation clinic and had frequent check-ups at least on a half-yearly basis, which assured a careful patient monitoring While ca areefu full pa ati tien ent mo en mon ni nitoring and early detection off malignancies. ma W Wh ilee th thee impact of immunosuppression malignancy formation remains like mmunosuppre mu ress sssio on on on m alig al ig gnanc nanccy fo form rm matio io on rema mainss chal ma cchallenging hallleeng ngiing ing an andd ddifferent ifffe ferrent rentt ooptions ptio ptio ionss llik ike k the CD4, agents CD D4, CD8, CD8 C D8,, CD16 C 16 or CD or CD20 CD20 cell cel e l count, coun co unt, t, the the cumulative ccum umul um u atiive dose ul doose of of the t e immunosuppressive th immu im munnosu nosuupp ppre ress ssiive ss ive ag gen entts ts oorr 60-62 62 the rejections have he number ooff bi bbiopsy opsy op sy pproven r ve ro venn re reje ject je c io ct ionss hhav avee be av been en n pproposed r po ro ose sedd60 , th thee nu numb number mber mb e ooff se er seve severe vere ve r rejectionss re is increasingly considered to be a valuable approach to reflect the grade of immunosuppression, as the dosing of the immunosuppressive drugs varies not only by body-weight but is also depending on individual liver metabolization.63,64 In view of the potential viral aetiology of cancer in transplant recipients, it is noteworthy that cytomegalovirus high-risk constellation (donor (D) +, recipient (R) Г) was similar in the statin and the control group. In addition, the primary outcome measure of this study, i.e. the occurrence of malignancy, might be influenced, by the occurrence of non-malignant events, cardiac death in particular. 13 Downloaded from http://circ.ahajournals.org/ by guest on June 9, 2014 DOI: 10.1161/CIRCULATIONAHA.111.081059 Indeed, such events are known as competing risk events and the Kaplan–Meier estimation procedure is not directly applicable under these conditions.65 As a consequence the cumulative incidence function for the event of interest was calculated by appropriately accounting for the presence of competing risk events. Conclusion Thus, in spite of limitations in adjusting for all potential confounders over a follow-up period of up to 25 years, when factors related to the era of transplantation like overall intensity of immunosuppression, and use of azathioprine might have changed, the results of the present study uggest, that statin use is associated with a substantial reduction of cancer risk and and nd all-cause all ll-c -cau -c ause au se suggest, mortality in heart transplantation recipients. Whet Wh ethherr these et thes th ese benefits of statins are specific speccif i ic for heart transplant tran nsp s laant recipients r Whether who are at part tic i ularly hig ighh ri iskk ooff ca can nce cerr an andd ca cann bbee eextrapolated xtrrapoolatedd to xt to aall lll ppatients attie ientts on on lon onngg-te term rm m particularly high risk cancer long-term mmu muno n su no supp ppre pp ress sssiv ve th herrap apy (p (par arti ar ticu ti cula cu larl r y ta rl tac crol olim im mus aand nd dm mTO TO OR in nhi hibi biito tors rs)) ne need e s to ed o bbee immunosuppressive therapy (particularly tacrolimus mTOR inhibitors) needs confirmed in n llong-term ongon g teerm gm rran ndo domi mize mi zedd cl ze cclinical inic in iccal ttrials. r al ri a s. s randomized Conflict of Interest Disclosures: Thomas F. LГјscher: receives research grants and honoraria from Pfizer. References: 1. Schaffer SA, Ross HJ. Everolimus: Efficacy and safety in cardiac transplantation. 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Pe Immunosuppressive level other carcinoma squamous mmu muno nosu supp ppre ress ssiv ivee le leve vell an andd ot othe herr ri risk sk ffactors acto ac tors rs ffor or bbasal asal as al ccell elll ca el carc rcin inom omaa an andd sq squa uamo mous us ccell elll el carcinoma in heart transplant recipients. Arch Dermatol. 2004;140:1079-1085. 61. Stalder M, Birsan T, Holm B, Haririfar M, Scandling J, Morris RE. Quantification of immunosuppression by flow cytometry in stable renal transplant recipients. Ther Drug Monit. 2003;25:22-27. 62. Caforio AL, Fortina AB, Piaserico S, Alaibac M, Tona F, Feltrin G, Pompei E, Testolin L, Gambino A, Volta SD, Thiene G, Casarotto D, Peserico A. Skin cancer in heart transplant recipients: Risk factor analysis and relevance of immunosuppressive therapy. Circulation. 2000;102:III222-227. 63. Moscoso-Solorzano GT, Ortega F, Rodriguez I, Garcia-Castro M, Gomez E, Diaz-Corte C, Baltar JM, Alvarez V, Ortiz A, Coto E. A search for cyclophilin-a gene variants in cyclosporine a-treated renal transplanted patients. Clin Transplant. 2008;22:722-729. 19 Downloaded from http://circ.ahajournals.org/ by guest on June 9, 2014 DOI: 10.1161/CIRCULATIONAHA.111.081059 64. Kagaya H, Miura M, Saito M, Habuchi T, Satoh S. Correlation of impdh1 gene polymorphisms with subclinical acute rejection and mycophenolic acid exposure parameters on day 28 after renal transplantation. Basic Clin Pharmacol Toxicol. 2010;107:631-636. 65. Satagopan JM, Ben-Porat L, Berwick M, Robson M, Kutler D, Auerbach AD. A note on competing risks in survival data analysis. Br J Cancer. 2004;91:1229-1235. Table 1. Patient characteristics. Categorical variables are presented as number of patients (%). Continuous variables are presented as median with 25th – 75th percentiles in brackets. The median follow-up for overall and event free survival is shown with 95% confidence intervals in brackets. n = 255 225 ((88)) 51 (44 – 57) 106 (45) 129 (55) Male, n ((%)) Age at time of transplantation (years) schemic cardiomyopathy (n, %) Ischemic Non-ischemic cardiomyopathy (n, %) CMV high risk constellation (recipient recipient negative/donor positive) (n, %) Immunosuppressive mmu muno mu nosu no supp su pprresssiv pp ivee therapy t erapy (n, %) th Calcineurin Cal Ca lcineuri lcin rin n iinhibitors nhiibi bito tors r Ev Everolimus ver e olimuss Azathioprine Az Prednisone Pr red e nisonee Mycophenolic Myco My coph co phen ph enol en olic ol ic acid acidd Swit tch tto o tacrolimus t cr ta c ol olim imus us ((n,%) n %)) n, Switch S wiitch h to mT mTOR OR inhibitors iinh nhib ibit itor ors (n ((n,%) ,%)) ,% Switch Follow-up Foll Fo llow ow-u up fo forr fr ffreedom eedo ee dom m from from ccan cancer ance cerr (yea ((years) years rs)) Tumors (n, % of all tumors) Skin Lymphoma Unknown Intestine Brain Bladder Breast Kidney Follow-up for overall survival (years) Cause of death (n, % of all patients) Cancer (n, % of deaths) Cardiovascular (n, % of deaths) Infection (n, % of deaths) Other (n, % of deaths) Rejections ISHT >IB (per year) Rejections > ISHT 2 (per year) 73 (31) (98) 2247 47 ((98 9 ) 2244 (1 (10) 0 179 79 9 ((71) 71)) 71 2232 32 2 ((93) 93)) (62) 1155 15 5 (6 62) 18 (7) 7) 28 ((11) 11)) 11 12.6 12 .6 (11.0 (11 (11 1.0 – 14.0) 114. 4.0) 0) 61 (56) 18 (17) 9 (9) 7 (6) 6 (6) 3 (3) 2 (2) 2 (2) 13.7 (12.8 – 14.8) 94 (37) 29 (31) 49 (52) 9 (10) 7 (7) 0.3 (0.1-0.6) 0.1 (0-0.3) 20 Downloaded from http://circ.ahajournals.org/ by guest on June 9, 2014 DOI: 10.1161/CIRCULATIONAHA.111.081059 Table 2. Characteristics of patients receiving statin therapy compared to those without statins. Categorical variables are presented as number of patients (%). Continuous variables are presented as median with 25th - 75th percentiles in brackets. Statin therapy (n=151) 134 (89) 52 (45–57) 125 (72-184) Male, n (%) Age at time of transplantation (years) Follow-up for freedom from cancer (months) Statin, n (%) Simvastatin No statin (n=104) 91 (88) 50 (41-56) 75 (40-127) p-value 0.84 0.70 0.55 35 (23) Fluvastatin Atorvastatin 6 (4) 28 (19) Pravastatin Statin related myopathy (all patients received high dose statin therapy) Discontinuation of statin therapy 82 (54) 5 (3) 2 (1) Immunosuppressive mmunosuppressive therapy (n, %) Calcineurin inhibitors Azathioprine 147 (97) 96 (64) 100 (9 (99) 9) 83 (83) 00.65 .65 65 0.002 Mycophenolic Myco My coph p en ph enol olic i aacid cidd ci Baseline Baaseli line li ne cho cholesterol hole lessterrol vval le values a ues (mmol/l)) 110 (74) 5.8 (4.9–6.1) (4.9– –6. 6 1) 45 (45) 5.5 ((5.0 5.0 – 6.7)) <0.001 0.50 (49) 699 (4 49) (39) 337 7 (39 9) Rejections ISHLT Rejeect ctio ionss IISH SHLT LT > IIB B (perr yyear) ea ar) (51) 711 ((5 51) 0.3 0.3 (0.1-0.6) (0.1-0 (0 0.6 .6)) (61) 588 ((61 611) 0.22 (0–0.6) (0–0 (0 –0.6)) 0.17 0 17 0. 7 Rejections ISHLT ISH SH HLT > 2 (per (pe perr year) yeear ar)) CMV high hi h risk i k constellation ll i ((n,%) %) 0.1 (0-0.3) 0 1 (0 0. (0-0 -0.3)) -0 37 (26) (0-0.4) 00.1 0. 1 (0 (0-0 -0.4 -0 .44) 36 (38) 0.23 00.08 08 54 (36) 32 (59) 54 (52) 29 (54) Lymphoma Unknown 7 (13) 6 (11) 11 (20) 3 (6) Intestine Brain 2 (4) 3 (6) 5 (9) 3 (6) Bladder Breast 2 (4) 0 1 (2) 2 (4) Kidney 2 (4) 37 (15) 0 57 (22) 10 (4) 19 (8) 19 (8) 30 (12) 4 (2) 4 (2) 5 (2) 3 (1) 00.13 0. 1 13 Cause transplantation %)) Cause Cau us of trans nspl plaant antatiion ((n, n, % Ischemic sch hem e ic cardiomyopathy cardiomyyop yopathyy Non-ischemic Noonn is isch chem micc cardiomyopathy car arddiom myo opaath thyy Tumors (n, % of all tumors within study group) Skin Cause of death (n, % of all patients) Cancer (n, % of deaths) Cardiovascular (n, % of deaths) Infection (n, % of deaths) Other (n, % of deaths) 21 Downloaded from http://circ.ahajournals.org/ by guest on June 9, 2014 DOI: 10.1161/CIRCULATIONAHA.111.081059 Table 3. Hazard ratios and confidence intervals of a Cox regression model investigating the time to tumor formation. Statin therapy Non-ischemic cardiomyopathy Age (per year) Male gender Calcineurin-inhibitor therapy Azathioprine therapy Mycophenolate therapy Switch to mTOR inhibitor (per year) Switch to Tacrolimus (per year) Hazard ratio 0.33 0.74 1.06 1.22 1.15 1.45 0.81 1.7 1.4 95% CI 0.21 – 0.51 0.48 – 1.14 1.04 – 1.10 0.45 – 3.3 0.11 – 12.4 0.87 – 2.4 0.47 – 1.37 0.34 -5.7 0.52 – 5.61 p-value <0.0001 0.17 <0.0001 0.7 0.91 0.15 0.42 0.64 0.38 Figure Legends: Figure 1. Cumulative incidence curves comparing tumor occurrence (p < 0.003) and death from mali ma lign li gnan gn antt vs an vs.. no onn-m malignant origin (p = 0.02) in n ppa atients receivin ng stat attin therapy compared to malignant non-malignant patients receiving statin patients pati ien e ts witho without. out ut.. Figure 2. Cum um mul u at ativ iv ve in nciide d nc n e of o ““skin” skkin in” (p p=0 0.2 2) vs. vs ““non-skin” nonno n sk nskin in” ma in mali lign li gnan gn anci an c ess ((p=0.04) ci p 0. p= 0.04 0 ) in Cumulative incidence (p=0.2) malignancies patients with statin - vs. no statin. Figure 3. Cumulative incidence curves comparing tumor occurrence (p=0.02) and death from malignant vs. non-malignant origin (p=0.007) in patients receiving statin therapy > 50% vs. < 50% of follow-up time. (TTC: time to cancer). Figure 4. Overall survival of patients receiving statin therapy compared to patients without such treatment (Log-rank p<0.0001). 22 Downloaded from http://circ.ahajournals.org/ by guest on June 9, 2014 Downloaded from http://circ.ahajournals.org/ by guest on June 9, 2014 Downloaded from http://circ.ahajournals.org/ by guest on June 9, 2014 Downloaded from http://circ.ahajournals.org/ by guest on June 9, 2014 Downloaded from http://circ.ahajournals.org/ by guest on June 9, 2014
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