Association of Androgen Deprivation Therapy With Cardiovascular Death in Patients With Prostate

REVIEWAssociation of Androgen Deprivation Therapy With Cardiovascular Deathin Patients With Prostate CancerA Meta-analysis of Randomized TrialsPaul L.Nguyen,MDYoujin Je,MSFabio A.B.Schutz,MDKaren E.Hoffman,MD,MPH,MHScJim C.Hu,MD,MPHArti Parekh,BAJoshua A.Beckman,MD,MScToni K.Choueiri,MDA N D R O G E N D E P R I V A T I O Ntherapy(ADT)in the form ofa gonadotropin-releasing hor-mone(GnRH)agonist is amainstay of prostate cancer treat-ment,but several studies have sug-gested that ADT may increase a pa-tient’s risk of dying from cardiovascularcauses.In2006,Keating et al1found thatGnRH agonist use was associated witha44%increased risk of incident diabe-tes,16%increase in coronary heartdisease,11%increase in myocardialinfarction(MI),and16%increase insudden cardiac death in the nationalSurveillance,Epidemiology,and EndResults–Medicare database.In2007,Tsai et al2found that ADT was associ-ated with a2.6-times increase in car-diovascular death among men receiv-ing radical prostatectomy in theCAPSURE database.In addition,D’Amico et al3reanalyzed data from2randomized trials and found that ADTuse was associated with a shorter time to fatal MI in a subgroup of men olderthan65years.On the basis of theseand other studies,4the American HeartAssociation,the American Cancer Author Affiliations are listed at the end of this article. Corresponding Author:Paul L.Nguyen,MD,Depart-ment of Radiation Oncology,Dana-Farber Cancer In-stitute,Brigham and Women’s Hospital,75Francis St, Boston,MA02115(pnguyen@).Context Whether androgen deprivation therapy(ADT)causes excess cardiovascu-lar deaths in men with prostate cancer is highly controversial and was the subject of ajoint statement by multiple medical societies and a US Food and Drug Administrationsafety warning.Objective To perform a systematic review and meta-analysis of randomized trialsto determine whether ADT is associated with cardiovascular mortality,prostate cancer–specific mortality(PCSM),and all-cause mortality in men with unfavorable-risk,non-metastatic prostate cancer.Data Sources A search of MEDLINE,EMBASE,and the Cochrane Central Registerof Controlled Trials databases for relevant randomized controlled trials in English be-tween January1,1966,and April11,2011.Study Selection Inclusion required nonmetastatic disease,intervention group withgonadotropin-releasing hormone agonist–based ADT,control group with no imme-diate ADT,complete information on cardiovascular deaths,and median follow-up ofmore than1year.Data Extraction Extraction was by2independent reviewers.Summary incidence,rela-tive risk(RR),and CIs were calculated using random-effects or fixed-effects models.Results Among4141patients from8randomized trials,cardiovascular death in pa-tients receiving ADT vs control was not significantly different(255/2200vs252/1941events;incidence,11.0%;95%CI,8.3%-14.5%;vs11.2%;95%CI,8.3%-15.0%;RR,0.93;95%CI,0.79-1.10;P=.41).ADT was not associated with excesscardiovascular death in trials of at least3years(long duration)of ADT(11.5%;95%CI,8.1%-16.0%;vs11.5%;95%CI,7.5%-17.3%;RR,0.91;95%CI,0.75-1.10;P=.34)or in trials of6months or less(short duration)of ADT(10.5%;95%CI,6.3%-17.0%;vs10.3%;95%CI,8.2%-13.0%;RR,1.00;95%CI,0.73-1.37;P=.99).Among4805patients from11trials with overall death data,ADT was associated with lowerPCSM(443/2527vs552/2278events;13.5%;95%CI,8.8%-20.3%;vs22.1%;95%CI,15.1%-31.1%;RR,0.69;95%CI,0.56-0.84;PϽ.001)and lower all-cause mor-tality(1140/2527vs1213/2278events;37.7%;95%CI,27.3%-49.4%;vs44.4%;95%CI,32.5%-57.0%;RR,0.86;95%CI,0.80-0.93;PϽ.001).Conclusion In a pooled analysis of randomized trials in unfavorable-risk prostate can-cer,ADT use was not associated with an increased risk of cardiovascular death butwas associated with a lower risk of PCSM and all-cause mortality.JAMA.2011;306(21):For editorial comment see p2382.©2011American Medical Association.All rights reserved.JAMA,December7,2011—Vol306,No.212359Society,the American Urological Association,and the American Society for Radiation Oncology issued a joint scientific report to raise awareness of the potential linkage between ADT and cardiovascular events and stated “at this point,it is reasonable,on the basis of the above data,to state that there may be a relation between ADT and cardiovascular events and death.”5 Similarly,the US Food and Drug Administration issued a safety warning on October20,2010,requiring label-ing on GnRH agonists warning about an“increased risk of diabetes and cer-tain cardiovascular diseases(heart attack,sudden cardiac death,stroke) in men receiving these medications for the treatment of prostate cancer.”6 However,other studies have not confirmed these findings7-9and,due to the significant controversy and clini-cal concern over this issue,we per-formed an up-to-date meta-analysis of randomized controlled trials to de-termine whether ADT is associated with cardiovascular mortality,pros-tate cancer–specific mortality(PCSM), and all-cause mortality in men with unfavorable-risk,nonmetastatic pros-tate cancer.METHODSSelection of StudiesWe reviewed MEDLINE and EMBASE citations between January1,1966,and April11,2011,and the Cochrane Central Register of Controlled Trials database through April11,2011.The search terms used were prostate cancer and(androgen deprivation or androgen suppression or hormone or gonadotro-pin),with the results limited to ran-domized controlled trials in the Eng-lish language.We included only trials focused on patients with nonmeta-static and non−hormone-refractory disease and that had an intervention group with immediate ADT and a con-trol group of patients receiving no immediate ADT.For inclusion in our study,the trial had to predominantly use a GnRH agonist,have adequate information on cardiovascular deaths, and have a median follow-up of at least1year.We required a GnRH ago-nist because the large observationalstudy by Keating et al1found an excessrisk of coronary heart disease,MI,andsudden cardiac death among menwho received GnRH agonists but notthose who received orchiectomy,andbecause orchiectomy is much lesscommonly used in modern practice.When more than1publication wasidentified from the same clinical trial,we used the most recent or completereport of that trial.Quality of the trialswas assessed using the Jadad/Oxfordquality scoring system.10For analysisof PCSM and all-cause mortality,werequired trials to report those2endpoints but did not require that theyreport cardiovascular mortality.Data Extractionand Clinical End PointsData abstraction was conducted inde-pendently by2investigators(P.L.N.andA.P.)according to the Preferred Re-porting Items for Systematic Reviewsand Meta-analyses statement11and anydiscrepancies between reviewers wereresolved by consensus.For each study,we extracted the following informa-tion:first author’s name,year of pub-lication,median age of patients,num-ber of enrolled patients,inclusioncriteria,treatment groups,type of ADT,duration of ADT,number of cardiovas-cular deaths in ADT and control groups,definition of cardiovascular death,me-dian follow-up,number of PCSMdeaths,and number of overall deaths.The definition of cardiovascular deathwas accepted as defined by the studyauthors.If it was not specifically de-fined in the study,then we includedevents broadly related to cardiac dis-ease and vascular disease.Definitionsof cardiovascular disease for each in-cluded study are shown in the T ABLE,alongside the study information.3,8,9,12-19Statistical AnalysisFor the calculation of incidence,thenumber of patients with cardiovascu-lar death and the number of patientswho were treated with ADT or pla-cebo were extracted from the indi-vidual selected clinical trials.The pro-portion of patients with those adverseoutcomes and95%CIs were derivedfrom each trial.We also calculated rela-tive risks(RRs)and95%CIs of cardio-vascular death in patients assigned toADT vs controls in the same trial.Tocalculate95%CIs,the variance of a log-transformed study-specific RR was de-rived using the␦method.For studiesreporting zero events in a treatment orcontrol group,we applied a classic half-integer continuity correction to calcu-late RR and variance.We then re-peated this for the end points of PCSMand all-cause mortality.Statistical heterogeneity among trialsincluded in the meta-analysis was as-sessed by using the Cochran Q statis-tic,and inconsistency was quantifiedwith the I2statistic[100%ϫ(Q−df)/Q],which estimates the percentage oftotal variation across studies due toheterogeneity rather than chance.20Theassumption of homogeneity was con-sidered invalid for PϽ.10.Summary in-cidence and RRs were calculated usingrandom-effects or fixed-effects mod-els depending on the heterogeneity ofincluded studies.When substantialheterogeneity was not observed,thesummary estimate calculated on the ba-sis of the fixed-effects model was re-ported by using the inverse variancemethod.When substantial heteroge-neity was observed,the summary esti-mate calculated on the basis of the ran-dom-effects model was reported byusing the DerSimonian and Lairdmethod that considers both within-study and between-study variations.21For studies with separate treatmentgroups evaluating varying durations ofADT,we combined the2ADT groupsfor the overall analysis.To determine the RR of cardiovas-cular death due to ADT within particu-lar groups,we performed subgroupanalyses on trials of short course(ADTforՅ6months)or long course(ADTforՆ3years),trials with median ageof younger than70years or70years orolder,and trials in which radiation wasused.To further test for variation in theRR of cardiovascular death due to ADTADT AND CARDIOVASCULAR DEATH IN PROSTATE CANCER2360JAMA,December7,2011—Vol306,No.21©2011American Medical Association.All rights reserved.by duration of ADT or median age of patients,we conducted a meta-regression analysis by modeling a log-transformed study-specific RR as a de-pendent variable and duration of ADT (Յ6months orՆ3years)or median age (Ͻ70orՆ70years)as an indepen-dent variable.In addition,publication bias was evaluated through funnel plots(ie,plots of study results against pre-cision)and with the Begg and Eggertests.Two-tailed PϽ.05was consid-ered statistically significant.All statis-tical analyses were performed by usingStata/SE version12.0software(StataCorp).RESULTSSelection of TrialsOur initial search yielded1041studies(268from MEDLINE,211fromEMBASE,and562from the CochraneCentral Register of Controlled Trials).After removing386duplicate studies,we evaluated the abstracts of655stud-Table.Baseline Characteristics and Number of CV Deaths for the Selected Trials of ADT in Nonmetastatic Prostate CancerSource MedianAge,yDefinition of CVDeath From Article StageADT MedianFollow-up,yTreatmentGroupsNo.ofPatientsNo.ofDeathsNo.ofPCSMDeathsNo.ofCVDeathsType LengthD’Amico et al,32008(DFCI95-096)73(range,49-82)Fatal MI T1b-T2b,N0Leuprolideϩflutamide6mo7.6(range,0.5-11.0)70GyϩADT1023041370Gy104441413Messing et al,122006(ECOG/EST3886)66(range,45-78)Two by vasculardisease(1ischemic bowel,1peripheral andCV);1bypulmonaryembolism;1bycerebrovasculardiseasepNϩGoserelin ororchiectomyLifelong11.9(range,9.7-14.5)RPϩADT471773RP5128251Bolla et al,132010(EORTC22863)71(IQR,67-75)70(IQR,65-75)CV death T1-T4,N0-1Goserelin3y9.1(IQR,5.1-12.6)70GyϩADT20780262270Gy2081125717Schro¨der et al,142009(EORTC30846)67(range,52-77)64(range,46-79)CV and other causes(excluded othercancers,infection,unknown causes,and prostatecancer deaths)T0-T4,pN1-3Zoladexϩcyproteroneacetate ororchiectomyLifelong a13ImmediateADT119966910DelayedADT115977010Studer et al,152006(EORTC30891)73(range,52-81)Death due to CVdiseasesT1-T4,N0-1Buserelinϩcyproteroneacetate ororchiectomyLifelong7.8ImmediateADT4922579488DeferredADT4932849997Efstathiou et al,82009(RTOG85-31)70Death from coronaryartery disease,CVdisease,CHF,cardiac arrest,cardiomyopathy,CV arrhythmia,MI,or suddendeathT3orpNϩGoserelin Lifelong8.1(range,0.2-15.1)70GyϩADT477269825270Gy46830611365Roach et al,92008(RTOG86-10)70(range,50-88)71(range,49-84)Death from MI,CHF,cardiac arrest,cardiac,arteriosclerotic CVdisease,orcardiopulmonaryarrestT2-T4,N0-1Goserelinϩflutamide4mo11.913.270GyϩADT224164653170Gy2321849626Denham et al,162011(TROG96.01)68(range,41-87)67(range,51-80)Cardiac death T2c-T4,N0Goserelinϩflutamide3-6mo10.6(IQR,6.9-11.6)66GyϩADT532198893666Gy2701367023Aus et al,172002(Aus)67(range,50-77)66(range,54-77)NA T1b-T3aNX,M0Triptorelinϩcyproteroneacetate3mo 6.8(range,0.67-8.7)ADTϩRP63113NARP alone6393NASchulman etal,182000(ESGNTPC)NA NA T2-T3,NxM0Goserelinϩflutamide3mo NA ADTϩRP19283NARP alone21085NAYee et al,192010(MSKCC)61(IQR,57-66)61(IQR,57-65)NA T1-T2,N0MxGoserelinϩflutamide3mo8.0(range,0.1-15.3)ADTϩRP72101NARP alone6450NAAbbreviations:ADT,androgen deprivation therapy;CHF,congestive heart failure;CV,cardiovascular;IQR,interquartile range;MI,myocardial infarction;NA,not applicable;PCSM,pros-tate cancer–specific mortality;RP,radical prostatectomy.a Median duration of ADT in the EORTC30846trial was5.1(95%CI,3.9-6.5)years for immediate ADT.b Median duration of ADT in the RTOG85-31trial was4.2years.ADT AND CARDIOVASCULAR DEATH IN PROSTATE CANCER ©2011American Medical Association.All rights reserved.JAMA,December7,2011—Vol306,No.212361ies.After evaluating the abstract of each study,637studies were excluded because they did not meet inclusion criteria.Subsequently,we carefully read the full text of each of the re-maining18trials and excluded1trial for having a follow-up of less than1 year(n=167patients)22and6trials (n=1105patients)22-28for no mention of mortality outcomes,which resulted in11trials with4805patients for PCSM and all-cause mortality end points.3,8,9,12-19Three of these trials (n=664patients)17-19had no informa-tion on cardiovascular deaths;there-fore,the remaining8trials(n=4141 patients)were ultimately selected for inclusion in the cardiovascular death meta-analysis.3,8,9,12-16Median follow-up in these8included trials ranged between7.6and13.2years.A detailed selection process is shown in F IGURE1.The baseline characteristics ofeach trial are shown in the Table.Allselected trials included patients withnonmetastatic disease who weretreated with immediate predomi-nantly GnRH-agonist–based ADT vsno immediate ADT.Local therapyconsisted of external beam radiation(5trials),surgery(4trials),or nolocal therapy(2trials).Three trialsincluded a substantial proportion ofpatients with lymph node involve-ment.The duration of ADT variedfrom3months to lifelong.Quality of the Studiesand Publication BiasAll trials included in the meta-analysis were randomized,multi-center,phase3trials.All of the trialswere open label and have all been pub-lished in full manuscript form.The Ja-dad/Oxford quality scales require adouble-blinded placebo for2of the5points.Because this would have re-quired sham injections,none of the11trials included a double-blinded pla-cebo;therefore,their maximum scorewas3out of5points(7trials),and4trials scored2out of5points.10No evi-dence of publication bias was detectedfor RR of cardiovascular death by eitherBegg test(P=.54)or Egger test(P=.11),or for the RR of PCSM(Begg test,P=.53;Egger test,P=.24),or for the RR of all-cause mortality(Begg test,P=.76;Eg-ger test,P=.72).Incidence and RRof Cardiovascular DeathAmong the2200patients who weretreated with ADT,there were255cardiovascular deaths.The overallincidence of cardiovascular deathwas11.0%(95%CI,8.3%-14.5%)inthe ADT group(heterogeneity test:Q=33.58;PϽ.001;I2=79.2%).Forthe control group,there were1941patients and252cardiovasculardeaths,for an overall incidence of11.2%(95%CI,8.3%-15.0%;hetero-geneity test:Q=33.81;PϽ.001;I2=79.3%).The corresponding RR ofcardiovascular death for ADT vs con-trol was not significant(RR,0.93;95%CI,0.79-1.10;P=.41).No sig-nificant heterogeneity was observedin the RR analysis of cardiovasculardeath(heterogeneity test:Q=5.12;P=.64;I2=0%).Results of individualtrials are shown in F IGURE2.Variation of Associationby Duration of ADTThree trials(DFCI95-096,3TROG96.01,16and RTOG86-109)with1464patients used ADT for6months or less(range,3-6months),and5trials(EORTC22863,13RTOG85-31,8EORTC30891,15EORTC30846,14andECOG/EST388612)with2667pa-tients used ADT for at least3years(range,3years to lifelong).Among pa-tients in short-course ADT trials,the in-cidence of fatal cardiovascular eventsfor ADT vs control was10.5%(95%CI,6.3%-17.0%)vs10.3%(95%CI,8.2%-13.0%),respectively,and the RR of car-diovascular death was1.00(95%CI,0.73-1.37;P=.99).Among patients inlong-course ADT trials,the incidenceof fatal cardiovascular events for ADTvs control was11.5%(95%CI,8.1%-16.0%)vs11.5%(95%CI,7.5%-17.3%),respectively,and the RR of car-diovascular death was0.91(95%CI,0.75-1.10;P=.34).When comparingthe RRs of cardiovascular death due toADT among long-course trials withshort-course trials,we did not observea statistically significant difference(P=.63).Variation of Associationby Median Age in StudyAmong the5trials with a median ageof70years or older(DFCI95-096,3RTOG85-31,8RTOG86-10,9EORTC22863,13and EORTC3089115),therewas no association between ADT andcardiovascular death(13.3%;95%CI,10.4%-16.7%;vs13.1%;95%CI,9.6%-17.6%;RR for ADT vs no ADT,0.95;95%CI,0.79-1.13;P=.53;test forheterogeneity:Q=3.49;P=.48;I2=0%).Among the3trials with a median ageof younger than70years(TROG96.01,16ECOG/EST3886,12andEORTC3084614),there was also no evi-dence of an association between ADTFigure1.Article SelectionADT indicates androgen deprivation therapy;GnRH,gonadotropin-releasing hormone.ADT AND CARDIOVASCULAR DEATH IN PROSTATE CANCER2362JAMA,December7,2011—Vol306,No.21©2011American Medical Association.All rights reserved.and cardiovascular death (7.1%;95%CI,5.4%-9.2%;vs 8.2%;95%CI,5.9%-11.3%;RR,0.88;95%CI,0.58-1.34;P =.55;test for heterogeneity:Q=1.53;P =.46;I 2=0%).When comparing the RRs of cardiovascular death due to ADT among trials with median age of younger than 70years vs 70years or older,we did not observe a statisti-cally significant difference (P =.77).Findings in Patients Who Received Radiation TherapyWhen analysis was limited to the 5trials in which definitive radiation was used (DFCI 95-096,3TROG 96.01,16RTOG 85-31,8RTOG 86-10,9and EORTC 2286313),there was also no evidence of excess cardiovascular death due to ADT (10.5%;95%CI,8.1%-13.6%;vs 11.5%;95%CI,9.8%-13.3%;RR,0.94;95%CI,0.76-1.17;P =.57;test for heteroge-neity:Q=3.87;P =.42;I 2=0%).Association of ADT With PCSMThere were 443PCSM deaths among 2527patients in the ADT group and 552PCSM deaths among 2278patients in the control group.The incidence of PCSM among men receiving ADT vs control was 13.5%(95%CI,8.8%-20.3%)vs 22.1%(95%CI,15.1%-31.1%).The RR was 0.69(95%CI,0.56-0.84;P Ͻ.001;heterogeneity test:Q=24.57;P =.006;I 2=59.3%),favor-ing ADT use (F IGURE 3).Association of ADT With Overall SurvivalThere were 1140total deaths among 2527patients in the ADT group and 1213total deaths among 2278pa-tients in the control group.The inci-dence of all-cause mortality among men receiving ADT vs control was 37.7%(95%CI,27.3%-49.4%)vs 44.4%(95%CI,32.5%-57.0%).The RR of death was 0.86(95%CI,0.80-0.93;P Ͻ.001;heterogeneity test:Q=16.86;P =.08;I 2=40.7%)(F IGURE 4).COMMENTWhether ADT causes excess cardio-vascular mortality in men with pros-tate cancer has been highly controver-sial for the last 5years and recently led to a joint statement by the Ameri-can Heart Association,the American Cancer Society,the American Uro-logical Association,and the American Society for Radiation Oncology that there may be a relationship between ADT and cardiovascular events and death,and a safety warning by the Food and Drug Administration requiring GnRH agonist manufactur-ers to warn about an increased risk of diabetes,heart attack,sudden cardiac death,and stroke.5,6Because most of the data raising concern about the effect of ADT on cardiovascular events and cardiovascular death has been retrospective,we performed ameta-analysis of prospective random-ized trials comparing immediate GnRH-agonist–based ADT vs no ADT or deferred ADT for men with non-metastatic,unfavorable-risk prostate cancer.In our study of 4141patients in 8randomized trials with median follow-up of 7.6to 13.2years,we could not find any evidence that ADT causes excess cardiovascular mortal-ity.Our study suggests that for the population as a whole,there is either no adverse effect of ADT on cardio-vascular mortality or the magnitude of this effect is likely rather small.In our analysis,we could not find a subgroup in which ADT was associ-ated with excess cardiovascular mor-tality.Specifically,we did not see an ex-cess risk of cardiovascular mortality due to ADT among men receiving short-course ADT (Յ6months),men receiv-ing long-course ADT (Ն3years),men receiving radiation,or in trials in which the median age of enrollment was 70years or older.As shown in some of the individual trials,our meta-analysis found that the use of ADT in men with unfavorable-risk prostate cancer is as-sociated with improved prostate can-cer–specific survival and overall sur-vival.Of note,these improved survival findings only apply to men with unfa-vorable-risk prostate cancer,because the trials analyzed generally did not contain men with low-risk disease,aFigure 2.Relative Risk of Cardiovascular Deaths Associated With ADT Among Patients With Prostate CancerRelative Risk (95% CI)No./Total No. of EventsSourceADT Control Relative Risk (95% CI)P Value D’Amico et al,3 2008 (DFCI 95-096)13/10213/104 1.02 (0.50-2.09).96Bolla et al,13 2010 (EORTC 22863)22/20717/208 1.30 (0.71-2.38).39Schröder et al,14 2009 (EORTC 30846)10/11910/1150.97 (0.42-2.23).94Studer et al,15 2006 (EORTC 30891)88/49297/4930.91 (0.70-1.18).4752/47765/468Efstathiou et al,8 2009 (RTOG 85-31)0.78 (0.56-1.10).17Roach et al,9 2008 (RTOG 86-10)31/22426/232 1.23 (0.76-2.01).40Denham et al,16 2011 (TROG 96.01)36/53223/2700.79 (0.48-1.31).37OverallTest for heterogeneity: Q = 5.12; P = .64; I 2 = 0%255/2200252/19410.93 (0.79-1.10).41Messing et al,12 2006 (ECOG/EST 3886)3/471/51 3.26 (0.35-30.2).30ADT indicates androgen deprivation therapy.The summary relative risk of cardiovascular deaths was calculated using a fixed-effects model.The size of the squares indicates the weight of the study,which is the inverse variance of the effect estimate.The diamond indicates the summary relative risk.ADT AND CARDIOVASCULAR DEATH IN PROSTATE CANCER©2011American Medical Association.All rights reserved.JAMA,December 7,2011—Vol 306,No.212363group for whom there is no compel-ling evidence that ADT improves sur-vival.Overall,the results of our study should be generally reassuring to most men with unfavorable-risk prostate cancer considering ADT,because it was associated with improved survival without a measurable excess in cardio-vascular mortality,but a few impor-tant points need to be raised.First,none of the trials were stratified by preexisting cardiovascular comorbid-ity;therefore,our study cannot exclude the possibility that a small subgroup of men with underlying car-diac disease (even if controlled)could experience excess cardiovascular mor-tality due to ADT.29For example,a post hoc reanalysis of one of the trials included in our meta-analysis (DFCI 95-0963)found that men with moder-ate to severe comorbidity (mainly car-diac)appeared to have poorer overall survival when treated with ADT and radiation vs radiation alone,although this difference was not statistically significant (P =.08).3In addition,a retrospective review of a large data set of men who were treated with brachytherapy-based radiation found that although 95%of the men were not harmed by ADT,the 5%of men with a prior history of MI or conges-tive heart failure (CHF)appeared to have a higher incidence of all-causeFigure 3.Relative Risk of Prostate Cancer–Specific Mortality Associated With ADT Among Patients With Prostate CancerRelative Risk (95% CI)No./Total No. of EventsSourceADT Control Relative Risk (95% CI)P Value Aus et al,17 2002 (Aus)3/633/63 1.00 (0.21-4.77)>.99D’Amico et al,3 2008 (DFCI 95-096)4/10214/1040.29 (0.10-0.86).03Bolla et al,13 2010 (EORTC 22863)26/20757/2080.46 (0.30-0.70)<.001Schröder et al,14 2009 (EORTC 30846)69/11970/1150.95 (0.77-1.18).65Studer et al,15 2006 (EORTC 30891)94/49299/4930.95 (0.74-1.23).70Yee et al,19 2010 (MSKCC)1/720/64 2.67 (0.11-64.4).373/1925/210Schulman et al,18 2000 (ESGNTPC)0.66 (0.16-2.71).5582/477113/468Efstathiou et al,8 2009 (RTOG 85-31)0.71 (0.55-0.92).009Roach et al,9 2008 (RTOG 86-10)65/22496/2320.70 (0.54-0.91).007Denham et al,16 2011 (TROG 96.01)89/53270/2700.65 (0.49-0.85).002OverallTest for heterogeneity: Q = 24.57; P = .006; I 2 = 59.3%443/2527552/22780.69 (0.56-0.84)<.001Messing et al,12 2006 (ECOG/EST 3886)7/4725/510.30 (0.15-0.64).002ADT indicates androgen deprivation therapy.The summary relative risk of prostate cancer–specific mortality was calculated using a random-effects model.The size of the squares indicates the weight of the study,which is the inverse variance of the effect estimate.The diamond indicates the summary relative risk.Figure 4.Relative Risk of All-Cause Mortality Associated With ADT AmongPatients With Prostate CancerRelative Risk (95% CI)No./Total No. of EventsSourceADT Control Relative Risk (95% CI)P Value Aus et al,17 2002 (Aus)11/639/63 1.22 (0.54-2.74).63D’Amico et al,3 2008 (DFCI 95-096)30/10244/1040.70 (0.48-1.01).06Bolla et al,13 2010 (EORTC 22863)80/207112/2080.72 (0.58-0.89).002Schröder et al,14 2009 (EORTC 30846)96/11997/1150.96 (0.85-1.08).46Studer et al,15 2006 (EORTC 30891)257/492284/4930.91 (0.81-1.02).09Yee et al,19 2010 (MSKCC)10/725/64 1.78 (0.64-4.93).278/1928/210Schulman et al,18 2000 (ESGNTPC) 1.09 (0.42-2.86).86269/477306/468Efstathiou et al,8 2009 (RTOG 85-31)0.86 (0.78-0.96).005Roach et al,9 2008 (RTOG 86-10)164/224184/2320.92 (0.83-1.02).13Denham et al,16 2011 (TROG 96.01)198/532136/2700.74 (0.63-0.87)<.001OverallTest for heterogeneity: Q = 16.86; P = .08; I 2 = 40.7%1140/25271213/22780.86 (0.80-0.93)<.001Messing et al,12 2006 (ECOG/EST 3886)17/4728/510.66 (0.42-1.04).07ADT indicates androgen deprivation therapy.The summary relative risk of all-cause mortality was calculated using a random-effects model.The size of the squares indicates the weight of the study,which is the inverse variance of the effect estimate.The diamond indicates the summary relative risk.ADT AND CARDIOVASCULAR DEATH IN PROSTATE CANCER2364JAMA,December 7,2011—Vol 306,No.21©2011American Medical Association.All rights reserved.。