资源描述
Received:September 6,2023.Revised:October 22,2023.Accepted:October 24,2023 The Author(s)2023.Published by Oxford University Press on behalf of The International Society of Sexual Medicine.This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License(https:/creativecommons.org/licenses/by-nc/4.0/),which permits non-commercial re-use,distribution,and reproduction in any medium,provided the original work is properly cited.Forcommercial re-use,please contact The Journal of Sexual Medicine,2023,00,127https:/doi.org/10.1093/jsxmed/qdad163Special ReportPrinceton IV consensus guidelines:PDE5 inhibitors andcardiac healthRobert A.Kloner,MD,PhD1,2,*,Arthur L.Burnett,MD,MBA3,Martin Miner,MD4,Michael J.Blaha,MD5,Peter Ganz,MD6,Irwin Goldstein,MD7,Noel N.Kim,PhD7,Tobias Kohler,MD8,Tom Lue,MD,ScD6,Kevin T.McVary,MD9,John P.Mulhall,MD,MSc10,Sharon J.Parish,MD11,12,Hossein Sadeghi-Nejad,MD13,Richard Sadovsky,MD14,Ira D.Sharlip,MD6,Raymond C.Rosen,PhD61Department of Cardiovascular Research Pasadena,Huntington Medical Research Institutes,CA 91105,United States2Department of Medicine,Keck School of Medicine at University of Southern California,Los Angeles,CA,United States3Department of Urology,Johns Hopkins University,Baltimore,MD,United States4Mens Health Center,Miriam Hospital,Providence,RI,United States5Cardiology and Epidemiology,Johns Hopkins Ciccarone Center for the Prevention of Cardiovascular Disease,Baltimore,MD,United States6Department of Medicine(PG);Department of Urology(TL,IDS);Department of Psychiatry and Behavioral Sciences,(RCR),University ofCalifornia,San Francisco,San Francisco,CA,United States7Department of Sexual Medicine,Institute for Sexual Medicine,Alvarado Hospital,San Diego,CA,United States8Mayo Clinic,Rochester,MN,United States9Center for Male Health,Stritch School of Medicine at Loyola University Medical Center,Maywood,IL,United States10Department of Surgery,Memorial Sloan Kettering Cancer Center,New York,NY,United States11Weill Cornell Medicine,New York,NY,United States12Department of Medicine and Psychiatry White Plains,Westchester Behavioral Health Center,NewYork-Presbyterian Hospital,NY,UnitedStates13Department of Urology NY,NYU Langone Grossman School of Medicine,NY,United States14Department of Family and Community Medicine,SUNY Downstate Health Sciences University,Brooklyn,NY,United States*Corresponding author:Huntington Medical Research Institutes,686 South Fair Oaks Avenue,Pasadena,CA 91105,United States.Email:robert.klonerhmri.orgAbstractBackground:In 1999,1 year after the approval of the first oral phosphodiesterase type 5(PDE5)inhibitor for the treatment of erectile dysfunction(ED),the first Princeton Consensus Conference was held to address the clinical management of men with ED who also had cardiovasculardisease.These issues were readdressed in the second and third conferences.In the 13 years since the last Princeton Consensus Conference,the experience with PDE5 inhibitors is more robust,and recent new data have emerged regarding not only safety and drugdrug interactions,but also a potential cardioprotective effect of these drugs.Aim:InMarch2023,aninterdisciplinarygroupofscientistsandpractitionersmetforthefourthPrincetonConsensusGuidelinesattheHuntingtonMedical Research Institutes in Pasadena,California,to readdress the cardiovascular workup of men presenting with ED as well as the approachto treatment of ED in men with known cardiovascular disease.Method:A series of lectures from experts in the field followed by Delphi-type discussions were developed to reach consensus.Outcomes:Consensus was reached regarding a number of issues related to erectile dysfunction and the interaction with cardiovascular healthand phosphodiesterase-5 inhibitors.Results:An algorithm based on recent recommendations of the American College of Cardiology and American Heart Association,including theuse of computed tomography coronary artery calcium scoring,was integrated into the evaluation of men presenting with ED.Additionally,theissue of nitrate use was further considered in an algorithm regarding the treatment of ED patients with coronary artery disease.Other topicsincluded the psychological effect of ED and the benefits of treating it;the mechanism of action of the PDE5 inhibitors;drugdrug interactions;optimizing use of a PDE5 inhibitors;rare adverse events;potential cardiovascular benefits observed in recent retrospective studies;adulterationof dietary supplements with PDE5 inhibitors;the pros and cons of over-the-counter PDE5 inhibitors;nonPDE5 inhibitor therapy for ED includingrestorative therapies such as stem cells,platelet-rich plasma,and shock therapy;other nonPDE5 inhibitor therapies,including injection therapyand penile prostheses;the issue of safety and effectiveness of PDE5 inhibitors in women;and recommendations for future studies in the fieldof sexual dysfunction and PDE5 inhibitor use were discussed.Clinical Implications:Algorithms and tables were developed to help guide the clinician in dealing with the interaction of ED and cardiovascularrisk and disease.Strengths and Limitations:Strengths include the expertise of the participants and consensus recommendations.Limitations included thatparticipants were from the United States only for this particular meeting.Conclusion:The issue of the intersection between cardiovascular health and sexual health remains an important topic with new studiessuggesting the cardiovascular safety of PDE5 inhibitors.Keywords:erectile dysfunction;phosphodiesterase type 5 inhibitors;cardiovascular risk factors;sexual dysfunction;major adverse cardiovascular events.2The Journal of Sexual Medicine,2023,Vol 00,Issue 00IntroductionTwenty-five years have passed since the first oral phosphodi-esterase type 5(PDE5)inhibitor was approved in the UnitedStates for the treatment of erectile dysfunction(ED),a mile-stone event in drug development and sexual medicine prac-tice.1Shortly after its approval,it became clear that newguidelines were needed for the clinical management of sexualdysfunction in patients with overt or latent cardiovasculardisease(CVD).To address this need,an interdisciplinary panelof experts was convened in Princeton,New Jersey,in June1999 to consider the available data at that time,and todevelop recommendations for clinical management of sexualdysfunction in patients with CVD.The findings and consensusrecommendations from this meeting were published in theAmerican Journal of Cardiology in 2000.2Two subsequentPrinceton meetings were convened in 2004 and 2010,withimportant additions and modifications to the guidelines.3,4The third Princeton Consensus Conference(P3)Recommen-dations focused on 2 central concepts:(1)men who presentwith ED may have the same cardiovascular(CV)risk factorsthat are associated with atherosclerotic CVD(ASCVD)andtherefore,an evaluation and management strategy for thepotential CV risk in men with ED was needed;and(2)theneed to re-evaluate and modify the cardiac risk associatedwith sexual activity itself,whether spontaneous or assistedby the use of PDE5 inhibitors.This included assessing thepatient s exercise capacity and stress testing,if indicated,toassure that men could achieve the physical demands of sexualactivity prior to prescribing treatment for ED.The P3 alsoaddressed the issue of testosterone replacement therapy andthe surrounding controversies.In the intervening decade since the most recent Prince-ton guidance,4new questions have arisen regarding optimaltreatment of sexual dysfunction in men with underlying orcomorbid CVD.Most importantly,there is now a far morerobust,long-term database of clinical experience in the use ofPDE5 inhibitors by men with ED,5with comprehensive safetyanalyses,including in-depth investigation of patients takinga variety of antihypertensive drugs or-blockers for benignprostatic hyperplasia(BPH),and also in men prescribed bothPDE5 inhibitors and nitrates(despite the contraindication).6,7There have been significant advances also in both basic andapplied science of PDE5 inhibition and nitric oxide regulation,in addition to mounting experience with PDE5 inhibitors usedfor other indications,such as pulmonary artery hypertensionin both men and women,in which PDE5 inhibitors are nowfirst-line therapy.Significant advances have also taken place innew treatment approaches for ED,including therapies derivedfrom regenerative medicine and shockwave therapy.Newguidelines have also been published for optimal evaluationof patients with multiple risk factors for ASCVD.8Thereare also emerging data on the use of PDE5 inhibitors inwomen,in addition to centrally acting compounds for treatingcomponents of female sexual dysfunction(FSD).Recently,there has been an emerging literature suggesting that PDE5inhibitors may have cardioprotective effects and may play arole in preventative cardiology.Princeton 4(P4)was convened on March 10 to 11,2023,at The Huntington Medical Research Institutes,a nonprofitbiomedical research facility in Pasadena,California.Theprogram content and presenters were determined by theorganizing committee(R.A.K.,R.C.R.,A.L.B.,M.M.),whichincluded senior investigators in cardiology(R.A.K.),urology(A.L.B.),sexual medicine(R.C.R.),and men s health(M.M.).A multispecialty group of U.S.experts was selected bythe organizing committee to critically evaluate our currentevidence base regarding the relationship between ED andCV health,to update the CV workup in the ED patient,reassess when and how to treat ED patients with knownCVD,and reassess the accuracy and relevance or previousPrinceton management algorithms.The panel also assessedthe overall safety and role of PDE5 inhibitors in relationshipto CV health,examining new studies indicating a potentialcardioprotective role of PDE5 inhibitors and preventativecardiology,and re-examining the role of PDE5 inhibitors inwomen.In addition,newer nonPDE5 inhibitor therapies forthe treatment of ED and FSD were considered.A noteworthyomission was the topic of testosterone replacement therapyand the surrounding controversy.Because there was an ongo-ing randomized,prospective,controlled study of testosteronereplacement therapy with CV outcomes as major endpoints,the results of which were forthcoming at the time of themeeting,the organizing committee thought it best to wait forthose results to become available before developing furtherclinical guidelines for testosterone use in men with ED orother conditions.Since the meeting,the results of this studyhave been published and are briefly discussed in the sectionon clinical management of ED.The meeting was funded byan unrestricted educational grant from Sanofi,whose staffwere not involved in the selection of speakers,topics,or anyaspect of the content of the meeting.Prior to the meeting,eachpanelist was responsible for providing a written summaryof published literature on their assigned topic,focusing onstudies published since the prior Princeton meeting.4Thesesummaries were then circulated in advance of the meetingand panelists presented major findings on each topic,alongwith panel discussion,during the open portion of the meetingon March 10.For the closed session on day 2,a modifiedDelphi approach was used to develop consensus on the majorrecommendations and management algorithms,following thesame process as in the previous consensus meetings.2-4We are deeply honored to dedicate the P4 to the memory ofProfessor Graham Jackson,MD,FESC,FRCP,FACC(1947-2016),whowasapioneerinthefieldoftheintersectionofsex-ual health and CV health.9His decades-long contributions tocardiology,sexual medicine,and men s health have served asa guiding inspiration to his many patients,colleagues,friends,and family.We honor Dr Jackson with heartfelt appreciationand are saddened by his loss.Epidemiology and pathophysiology revisitedSexual activity and cardiac risk:can he climb 2flights of stairs?A major issue of concern for the 1999 Princeton ConsensusConference2was the cardiac load or stress on the heartthat is likely to occur with sexual intercourse or other sex-ual activity.2This is especially relevant for men with pre-existing CV conditions,including angina pectoris,congestiveheart failure,arrhythmias,and others.Epidemiologic dataavailable at the time indicated a slight,albeit statisticallysignificant association between sexual activity and incidentcardiac events.10However,the absolute risk differences wereestimated to be minimal:“In the United States,a 50-year-oldThe Journal of Sexual Medicine,2023,Vol 00,Issue 003man has a baseline annual risk of myocardial infarction(MI)of about 1%,which increases to only 1.01%as a consequenceof sexual activity.”The annual risk associated with sexualactivity increases to only 1.10%,even in high-risk men withknown CVD or risk factors.2In a subsequent meta-analysis of10 confirmatory studies,the absolute risk increase associatedwith 1 hour of additional physical or sexual activity per weekwas estimated as 2 to 3 per 10 000 person-years for MI and1 per 10 000 person-years for sudden cardiac death.Regularexercise was found in this meta-analysis to further attenuatethis marginally increased risk.11Based on available evidence,P1 panelists concluded thatsexual intercourse or activity of approximately 30 minutesduration with a usual partner in a long-standing relationshipcorresponds to a workload of approximately 2 to 3 metabolicequivalents of task(METS)and would not normally posea greater risk than climbing 2 flights of stairs without car-diac symptoms.2For patients who fail to meet this simplebenchmark,further cardiac assessment is indicated,includinga simple exercise stress test to confirm the patient s self-reportof exercise intolerance.Conclusions reached by P1 concerningcardiac risk of sexual activity were incorporated into the P2and P3 guidelines2-4and are retained in the current version.Itshould be noted that in more recent analyses,some estimatesreport higher expenditures of METS for moderately intensesexual activity in young couples of 5 to 6 METS,whichcorresponds to about 4 minutes on a standard Bruce ProtocolTreadmill Test.12In younger individuals with CV risk factors,5 to 6 METS on a treadmill without evidence of ischemiasuggests that,in general,sexual activity is safe.Erectile dysfunction and CVD:is ED a harbinger offuture events?Epidemiologic studies have examined the association betweenED and CV risk factors generally and its predictive relation-ship to MI,stroke,cardiac death,and other major CV out-comes(see Table 1).13-21For example,it has been found thatED symptoms precede clinically evident CVD by as long as 2to 5 years,making the diagnosis of ED especially useful as amarkerofprobablesubclinicalCVD.14,15InmenwithED,butwithout overt cardiac symptoms,cardiac events occurred in4.2%of men within 2 years of incident ED and 12.3%of menat 5 years.15In another study,incident ED was associated withan adjusted hazard ratio of 1.25(95%CI=1.02-1.53;p=0.04)for subsequent car
展开阅读全文
浙ICP备2021020529号-1 | 浙B2-20240490 
