Successfully reported this slideshow.
We use your LinkedIn profile and activity data to personalize ads and to show you more relevant ads. You can change your ad preferences anytime.
ORIGINAL CONTRIBUTIONONLINE FIRSTEffect of Phosphodiesterase-5 Inhibitionon Exercise Capacity and Clinical StatusinHeartFa...
HEART FAILURE WITH PRE-served ejection fraction(HFPEF) or diastolic heartfailure is a common andhighlymorbidcondition.1Cli...
treatment effect) was 95. Other second-ary end points included change in6-minute walk distance at 24 weeks andchangeinpeak...
Table 1. Baseline Characteristics of the PatientsNo. (%) of PatientsAll (N = 216) Placebo (n = 103) Sildenafil (n = 113)Ag...
The heart failure questionnaire scorewas consistent with the distribution ofNew York Heart Association functionalclass obs...
proBNP, with or without atrial fibril-lation or treated or not with renin-angiotensin system antagonists,␤-blockers, or st...
eling, diastolic function parameters, orpulmonary artery systolic pressure. Re-nal function worsened more and NT-proBNP, e...
tihypertrophic effects in mice with lesssevere pressure overload and compen-sated left ventricular hypertrophy withrelativ...
Published Online: March 11, 2013. doi:10.1001/jama.2013.2024Author Affiliations: Department of Medicine, MayoClinic, Roche...
8. Guazzi M, Vicenzi M, Arena R, Guazzi MD. Pul-monary hypertension in heart failure with preservedejection fraction: a ta...
Upcoming SlideShare
Loading in …5

RELAX: Inhibidor de la fosfodiesterasa-5. Insuficiencia cardiaca con función ventricular preservada


Published on

Dra. Margaret Redfield. Congreso ACC 2013, Estados Unidos. RELAX: Inhibidor de la fosfodiesterasa-5 no mostró beneficio en la insuficiencia cardiaca con función ventricular preservada. Encuentre más presentaciones de este congreso en la página oficial de SOLACI:

Published in: Health & Medicine, Business
  • Be the first to comment

  • Be the first to like this

RELAX: Inhibidor de la fosfodiesterasa-5. Insuficiencia cardiaca con función ventricular preservada

  1. 1. ORIGINAL CONTRIBUTIONONLINE FIRSTEffect of Phosphodiesterase-5 Inhibitionon Exercise Capacity and Clinical StatusinHeartFailureWithPreservedEjectionFractionA Randomized Clinical TrialMargaret M. Redfield, MDHorng H. Chen, MDBarry A. Borlaug, MDMarc J. Semigran, MDKerry L. Lee, PhDGregory Lewis, MDMartin M. LeWinter, MDJean L. Rouleau, MDDavid A. Bull, MDDouglas L. Mann, MDAnita Deswal, MDLynne W. Stevenson, MDMichael M. Givertz, MDElizabeth O. Ofili, MDChristopher M. O’Connor, MDG. Michael Felker, MDSteven R. Goldsmith, MDBradley A. Bart, MDSteven E. McNulty, MSJenny C. Ibarra, MSNGrace Lin, MDJae K. Oh, MDManesh R. Patel, MDRaymond J. Kim, MDRussell P. Tracy, PhDEric J. Velazquez, MDKevin J. Anstrom, PhDAdrian F. Hernandez, MDAlice M. Mascette, MDEugene Braunwald, MDfor the RELAX TrialAuthor Affiliations are listed at the end of thisarticle.Corresponding Author: Margaret M. Redfield, MD,Division of Cardiovascular Diseases, Mayo Clinic, 200First St SW, Guggenheim 9, Rochester, MN 55905( Studies in experimental and human heart failure suggest that phos-phodiesterase-5 inhibitors may enhance cardiovascular function and thus exercise ca-pacity in heart failure with preserved ejection fraction (HFPEF).Objective To determine the effect of the phosphodiesterase-5 inhibitor sildenafil com-pared with placebo on exercise capacity and clinical status in HFPEF.Design Multicenter,double-blind,placebo-controlled,parallel-group,randomizedclini-cal trial of 216 stable outpatients with HF, ejection fraction Ն50%, elevated N-terminalbrain-typenatriureticpeptideorelevatedinvasivelymeasuredfillingpressures,andreducedexercisecapacity.ParticipantswererandomizedfromOctober2008throughFebruary2012at 26 centers in North America. Follow-up was through August 30, 2012.Interventions Sildenafil (n=113) or placebo (n=103) administered orally at 20 mg,3 times daily for 12 weeks, followed by 60 mg, 3 times daily for 12 weeks.Main Outcome Measures Primary end point was change in peak oxygen consump-tion after 24 weeks of therapy. Secondary end points included change in 6-minute walkdistance and a hierarchical composite clinical status score (range, 1-n, a higher value in-dicates better status; expected value with no treatment effect, 95) based on time to death,time to cardiovascular or cardiorenal hospitalization, and change in quality of life for par-ticipants without cardiovascular or cardiorenal hospitalization at 24 weeks.Results Median age was 69 years, and 48% of patients were women. At baseline,median peak oxygen consumption (11.7 mL/kg/min) and 6-minute walk distance (308m) were reduced. The median E/e (16), left atrial volume index (44 mL/m2), and pul-monary artery systolic pressure (41 mm Hg) were consistent with chronically elevatedleft ventricular filling pressures. At 24 weeks, median (IQR) changes in peak oxygen con-sumption (mL/kg/min) in patients who received placebo (Ϫ0.20 [IQR, Ϫ0.70 to 1.00])or sildenafil (Ϫ0.20 [IQR, Ϫ1.70 to 1.11]) were not significantly different (P=.90) inanalyses in which patients with missing week-24 data were excluded, and in sensitivityanalysis based on intention to treat with multiple imputation for missing values (meanbetween-group difference, 0.01 mL/kg/min, [95% CI, Ϫ0.60 to 0.61]). The mean clini-cal status rank score was not significantly different at 24 weeks between placebo (95.8)and sildenafil (94.2) (P=.85). Changes in 6-minute walk distance at 24 weeks in pa-tients who received placebo (15.0 m [IQR, Ϫ26.0 to 45.0]) or sildenafil (5.0 m [IQR,Ϫ37.0 to 55.0]; P=.92) were also not significantly different. Adverse events occurred in78 placebo patients (76%) and 90 sildenafil patients (80%). Serious adverse events oc-curred in 16 placebo patients (16%) and 25 sildenafil patients (22%).Conclusion and Relevance Among patients with HFPEF, phosphodiesterase-5 in-hibition with administration of sildenafil for 24 weeks, compared with placebo, didnot result in significant improvement in exercise capacity or clinical status.Trial Registration Identifier: NCT00763867JAMA. 2013;309(12):doi:10.1001/jama.2013.2024©2013 American Medical Association. All rights reserved. JAMA, Published online March 11, 2013 E1Downloaded From: on 03/11/2013
  2. 2. HEART FAILURE WITH PRE-served ejection fraction(HFPEF) or diastolic heartfailure is a common andhighlymorbidcondition.1Clinicaltrialsof renin-angiotensin system antago-nists have not demonstrated improve-ment in outcomes or clinical status inHFPEF, and effective therapies areneeded.2Phosphodiesterase-5 (PDE-5)metabolizes the nitric oxide and natri-uretic peptide systems’ second messen-gercyclicguanosinemonophosphateandthusmaylimitbeneficialnitricoxideandnatriuretic peptide actions in the heart,vasculature, and kidneys.Preclinical studies suggest thatinhibition of PDE-5 reverses adversecardiacstructuralandfunctionalremod-eling and enhances vascular, neuroen-docrine, and renal function.3In clini-cal studies, PDE-5 inhibitor therapyimproved exercise tolerance and clini-calstatusinpatientswithidiopathicpul-monary arterial hypertension and inpatients with heart failure and reducedejection fraction.4-7A small, single-center study of HFPEF observedimprovedhemodynamics,leftventricu-lar diastolic function, right ventricularsystolicfunction,leftventricularhyper-trophy, and lung function with 6 to 12months of therapy with a PDE-5 inhibi-tor compared with placebo.8In aggre-gate, these studies suggest the poten-tial for PDE-5 inhibition to ameliorateseveral key pathophysiological pertur-bations in HFPEF, and thus improveexercise capacity and clinical status.Accordingly, the Phosphodiester-ase-5 Inhibition to Improve Clinical Sta-tus and Exercise Capacity in Heart Fail-ure with Preserved Ejection Fraction(RELAX) trial was designed to test thehypothesis that, compared with pla-cebo, therapy with the PDE-5 inhibi-tor sildenafil would improve exercisecapacity in HFPEF after 24 weeks oftherapy, assessed by the change in peakoxygen consumption.METHODSStudy OversightAll study participants provided writ-ten informed consent prior to screen-ing. The National Heart, Lung, andBlood Institute–sponsored Heart Fail-ure Clinical Research Network con-ceived, designed, and conducted theRELAX trial. The trial protocol was ap-proved by a National Heart, Lung, andBlood Institute–appointed protocol re-view committee and data and safetymonitoring board, and by the institu-tional review board at each participat-ing site. The Duke Clinical Research In-stitute served as the data coordinatingcenter.Study DesignThe rationale for, and design of, theRELAX trial have been described.3Pa-tients with normal (Ն50%) ejectionfraction and heart failure with NewYork Heart Association functional classII through IV whose symptoms arestable while receiving medical therapywere eligible to participate if they hadobjective evidence of heart failure (pre-vious heart failure hospitalization, oracute heart failure therapy with intra-venous diuretic therapy, or chronic loopdiuretic therapy for heart failure withleft atrial enlargement, or invasivelydocumented elevation in left ventricu-lar filling pressures).A peak oxygen consumption of 60%or less of the age- and sex–specific nor-mal value9with a respiratory ex-change ratio of 1.0 or more at the car-diopulmonary exercise test screening,and either elevated (Ն400 pg/mL) N-terminal fragment of the precursor tobrain-type natriuretic peptide (NT-proBNP) level or elevation in left ven-tricular filling pressures at the time ofan NT-proBNP level less than 400pg/mL were required for study entry.A complete list of the trial inclusion andexclusion criteria is provided in the on-line supplement (eTable 1, available at As required infederally funded trials, a self-identification of investigator-definedrace or ethnicity option was recorded.Participants who met screening cri-teria underwent baseline studies (his-tory and physical examination, cardio-pulmonary exercise test, 6-minute walkdistance, Minnesota Living with HeartFailure Questionnaire, echocardiogra-phy, cardiac magnetic resonanceimaging [CMRI, if sinus rhythm], andphlebotomy for biomarkers), and werethen randomly assigned, in a 1:1 ratio,to receive either sildenafil or placebowith the use of an automated web-based system. A permuted block ran-domization scheme was used withstratification according to clinical siteand the presence of atrial fibrillation.Study drug was administered orallyat 20 mg, 3 times daily for 12 weeks.At the end of 12 weeks, each patient’shistory and physical examination, car-diopulmonary exercise test, 6-minutewalk distance, and heart failure ques-tionnairewererepeated.Phlebotomyforsildenafil levels was performed 2 hoursafter a scheduled dose of the study drugwere obtained. The dose was then in-creased to 60 mg, 3 times daily for 12weeks, after which baseline studies wererepeated, including phlebotomy forsildenafil levels 2 hours after study drug.If adverse effects developed, study staffcould recommend discontinuation orreturn to a lower or previously toler-ated dose of the study drug.Blinded core laboratories assessedbiomarkers (University of Vermont),cardiopulmonary exercise tests (Mas-sachusetts General Hospital, HarvardUniversity), CMRIs (Duke Univer-sity), and echocardiograms (MayoClinic).Study End PointsThe primary end point was the changein peak oxygen consumption after 24weeks of therapy. A number of sub-group analyses were prespecified. Sec-ondary end points included a compos-ite hierarchical-rank clinical score inwhich patients were ranked (range, 1-nwith data) based on time to death(tier 1), time to hospitalization forcardiovascular or cardiorenal causes(tier2),andchangeinheartfailureques-tionnaire from baseline (tier 3) for pa-tients without cardiovascular or cardio-renal hospitalization after 24 weeks oftherapy.10Because 189 patients had datafor this end point, the anchor value(mean value in each group indicating noPHOSPHODIESTERASE-5 INHIBITION IN HEART FAILUREE2 JAMA, Published online March 11, 2013 ©2013 American Medical Association. All rights reserved.Downloaded From: on 03/11/2013
  3. 3. treatment effect) was 95. Other second-ary end points included change in6-minute walk distance at 24 weeks andchangeinpeakoxygenconsumptionand6-minute walk distance after 12 weeksof therapy. Peak sildenafil levels at 12and 24 weeks and coinciding plasma cy-clic guanosine monophosphate levels at24weekswereassessed.Usingotherpre-specified end points, we assessed the ef-fect of PDE-5 inhibition on left ventricu-lar structure and vascular function byCMRI,Doppler-estimateddiastolicfunc-tion parameters and pulmonary arterysystolic pressure, and biomarkers thatreflect renal and neuroendocrine func-tion, oxidative stress, and collagenmetabolism.The percent-predicted peak oxygenconsumption, 6-minute walk dis-tance, and the presence of chrono-tropic incompetence and left ventricu-lar hypertrophy were calculated usingpublished criteria (eMethods).11-14Statistical AnalysisPowercalculationswerebasedonthestan-darddeviationforchangeinpeakoxygenconsumption and the magnitude of itschange when associated with improve-mentsinothermarkersofclinicalstatus(New York Heart Association class,6-minutewalkdistance,andqualityoflifescores) in heart failure trials.5,14,15Basedon these studies, a difference betweentreatmentgroupsof1.2mL/kg/mininthechangeinpeakoxygenconsumptionwasconsidered clinically significant.We estimated a 20% rate of incom-plete primary end point data due todeath, withdrawal, or incidence of newfactors limiting ability to exercise. Usinga 2-sample t test and a 2-sided ␣ valueof .05, a sample size of 190 patients had85% power to detect a difference of 1.2mL/kg/min in change in peak oxygenconsumption, assuming 20% missingdata and a standard deviation of changein peak oxygen consumption of 2.5 mL/kg/min. As an early-blinded interimanalysis of aggregated primary endpoint completeness indicated that themissingness rate approached 20%, theblinded investigators recommended in-creasing the sample size to 215 patients.The primary analyses were 2-sided,and patients without 24-week data wereexcluded. Sensitivity analysis for the pri-mary end point was based on the inten-tion to treat principle and utilized mul-tiple imputations with 100 imputed datasetstoaccountformissing24-weekdata.In addition, a prespecified “last obser-vationcarriedforward”sensitivityanaly-sisused“carry-forward”of12-weekdataif 24-week data were missing.Data are presented as median (inter-quartile range [IQR]). For the com-parison of treatment groups in theprimary analysis, a multivariable linear-regression model was used adjusting forbaseline peak oxygen consumption. Asimilar approach was used for the sec-ondary end point of change in 6-min-ute walk distance, adjusting for base-line 6-minute walk distance. For thecomposite hierarchical-rank clinicalscore, patients were ranked indepen-dent of treatment assignment from 1(worst outcome—the earliest death) ton (best outcome—survival with no car-diovascular or cardiorenal hospitaliza-tion, and the most favorable improve-ment in heart failure questionnaire) andtreatments compared using the Wil-coxon rank sum test. For primary andsecondary end points, a P value lessthan .05 was considered significant. Forsubgroup analyses, a treatment by sub-group interaction P less than .001 wasconsidered significant.All analyses were conducted with theuseofSASstatisticalsoftware,version9.2.RESULTSPatient PopulationA total of 216 patients were enrolled inthe trial from October 13, 2008, throughFebruary 21, 2012, at 26 sites in theUnitedStatesandCanada(FIGURE). Thebaseline characteristics were not sig-nificantly different between treatmentgroups except for a lower prevalence ofhypertension in the sildenafil group(TABLE 1). Patients in this study wereolder, 48% women, and obese with con-trolled blood pressure and multiple co-morbidities including hypertension, is-chemic heart disease, atrial fibrillation,diabetes, anemia, and chronic kidneydisease.Figure. Flow of Patients Through the Trial94 Included in the primary analysis9 Excluded5 Withdrew consent2 Unable to perform exercise test1 Unwilling to perform exercise test1 Had inadequate peak oxygen consumption data91 Included in the primary analysis22 Excluded9 Withdrew consent7 Unable to perform exercise test2 Unwilling to perform exercise test1 Had inadequate peak oxygen consumption data3 Died98 Completed 24-week follow-up visit82 Completed study per protocol16 Did not complete study per protocol3 Discontinued study drugb13 Reduced dosage of study drug101 Completed 24-week follow-up visit74 Completed study per protocol27 Did not complete study per protocol8 Discontinued study drugc19 Reduced dosage of study drug5 Did not complete 24-week follow-up visit(withdrew consent)b12 Did not complete 24-week follow-up visit9 Withdrew consentc3 Died103 Randomized to receive placebo103 Received placebo as assigned113 Randomized to receive sildenafil113 Received sildenafil as assigned216 Outpatients with heartfailure randomizedaSome patients discontinued study drug for a specific reason (Ͼ1 may apply) and later withdrew.aData regarding the number of patients screened for eligibility was not collected.bStudy drug discontinued due to adverse event (1), physician decision (1), other (2), or for withdrawal of con-sent (4).cStudy drug discontinued due to adverse event (9), physician decision (1), other (5), or for withdrawal of con-sent (5).PHOSPHODIESTERASE-5 INHIBITION IN HEART FAILURE©2013 American Medical Association. All rights reserved. JAMA, Published online March 11, 2013 E3Downloaded From: on 03/11/2013
  4. 4. Table 1. Baseline Characteristics of the PatientsNo. (%) of PatientsAll (N = 216) Placebo (n = 103) Sildenafil (n = 113)Age, median (IQR), y 69 (62-77) 69 (62-77) 68 (62-77)Women 104 (48) 55 (53) 49 (43)Self-reported white race 197 (91) 95 (92) 102 (90)BMI, median (IQR) 32.9 (28.3-39.1) 32.8 (28.6-38.6) 33.3 (28.2-40.0)NYHA functional classificationII 101 (47) 46 (45) 55 (49)III 115 (53) 57 (55) 58 (51)MLHFQ total score, median (IQR) 43 (30-62) 43 (29-58) 44 (30-63)Systolic blood pressure, median (IQR), mm Hg 126 (113-138) 127 (113-138) 124 (113-138)Heart rate, median (IQR), beats/min 69 (61-78) 68 (62-77) 70 (61-80)Jugular venous pressure Ն8 cma 95/209 (45) 48/99 (48) 47/110 (43)Edema 125 (58) 61 (59) 64 (57)Ն1 Heart failure hospitalizations in previous year 79 (37) 40 (39) 39 (35)Qualifying ejection fraction, median (IQR), % 60 (55-66) 60 (55-65) 60 (55-66)Medical historyHypertension 183 (85) 93 (90) 90 (80)Ischemic heart disease 84 (39) 37 (36) 47 (42)Atrial fibrillation or flutter 111 (51) 52 (50) 59 (52)Diabetes mellitus 93 (43) 45 (44) 48 (42)COPD 42 (19) 20 (19) 22 (19)Anemiab 76 (35) 34 (33) 42 (38)Local laboratory creatinine, median (IQR), mg/dL 1.2 (0.9-1.5) 1.1 (0.9-1.5) 1.3 (1.0-1.5)Glomerular filtration rate, median (IQR), mL/min/1.73 m257 (43-75) 59 (43-76) 57 (43-70)Stage 3/4 chronic kidney disease 119 (55) 56 (54) 63 (56)Medications at enrollmentLoop diuretic 166 (77) 79 (77) 87 (77)Any diuretic 186 (86) 86 (83) 100 (88)ACE inhibitor or angiotensin II receptor blocker 152 (70) 78 (76) 74 (65)␤-Blocker 164 (76) 77 (75) 87 (77)Aldosterone antagonist 23 (11) 9 (9) 14 (12)Calcium channel blocker 66 (31) 35 (34) 31 (27)Statin 138 (64) 67 (65) 71 (63)Core laboratory biomarker dataCystatin C, median (IQR), mg/Lc 1.31 (1.07-1.74) 1.34 (1.08-1.76) 1.29 (1.04,1.70)NT-proBNP, median (IQR), pg/mLd 700 (283-1553) 648 (247-1679) 757 (318-1465)Aldosterone, median (IQR), ng/dLc 18.9 (11.8-28.3) 18.0 (11.4-29.4) 20.7 (13.0-27.5)Endothelin-1, median (IQR), pg/mLc 2.36 (1.95-3.20) 2.37 (2.03-3.14) 2.35 (1.85-3.22)NT-procollagen III, median (IQR), ␮g/Lc 7.7 (6.1-10.0) 7.9 (6.4-11.2) 7.5 (5.5-9.3)Uric acid, median (IQR), mg/dLe 7.4 (5.8-8.5) 7.1 (5.8-8.5) 7.5 (5.8-8.5)Peak functional statusOxygen consumption, median (IQR), mL/kg/minf 11.7 (10.2-14.4) 11.9 (10.1-14.4) 11.7 (10.4-14.5)Predicted peak oxygen consumption, median (IQR), % 41 (35-49) 41 (36-49) 41 (34-48)Respiratory exchange ratio, median (IQR)f 1.09 (1.02-1.15) 1.10 (1.03-1.15) 1.09 (1.02-1.16)Systolic blood pressure, median (IQR), mm Hgg 156 (132-170) 154 (134-168) 156 (130-170)Chronotropic incompetencef 164 (77) 79 (78) 85 (76)6-Minute walk distance, median (IQR), m 308 (229-383) 305 (213-372) 308 (241-392)Predicted 6-minute walk distance, median (IQR), % 69 (51-83) 68 (48-83) 70 (54-83)Abbreviations: ACE, angiotensin-converting enzyme; BMI, body mass index, calculated as weight in kilograms divided by height in meters squared; COPD, chronic obstructivepulmonary disease; IQR, interquartile range; MLHFQ, Minnesota Living with Heart Failure Questionnaire; NT-proBNP, N-terminal fragment of the precursor to brain-type natri-uretic peptide; NYHA, New York Heart Association.SI conversion factors: To convert aldosterone from ng/dL to pmol/L, multiply by 27.74; creatinine from mg/dL to ␮mol/L, multiply by 88.4; and uric acid from mg/dL to ␮mol/L,multiply by 59.485.aIndicates the number of patients/number of patients with nonmissing data for the variable (percentage).bAnemia is defined as hemoglobin Ͻ13 g/dL for men, and Ͻ12 g/dL for women.cAvailable in 214 (102 placebo and 112 sildenafil-treated) patients.dAvailable in 213 (101 placebo and 112 sildenafil-treated) patients.eAvailable in 212 (101 placebo and 111 sildenafil-treated) patients.fAvailable in 215 (103 placebo and 112 sildenafil-treated) patients due to technical limitation precluding core laboratory measurement of peak oxygen consumption.gAvailable in 209 (99 placebo and 110 sildenafil-treated) patients.PHOSPHODIESTERASE-5 INHIBITION IN HEART FAILUREE4 JAMA, Published online March 11, 2013 ©2013 American Medical Association. All rights reserved.Downloaded From: on 03/11/2013
  5. 5. The heart failure questionnaire scorewas consistent with the distribution ofNew York Heart Association functionalclass observed in the study population.Evidence of volume overload (elevatedjugular venous pressure or edema) andhospitalizationforheartfailureinthepre-vious year were common. The majorityof patients were taking diuretics, renin-angiotensinsystemantagonists,␤-block-ers, and statins. There was evidence ofneuroendocrine activation and alteredcollagen metabolism as levels of NT-proBNP, aldosterone, endothelin-1, andNT-procollagen III exceeded referenceranges(eTable2,availableat and chronotropic incompe-tence was common.Baseline echocardiographic andCMRI characteristics of the patientswere not significantly different be-tween treatment groups (TABLE 2). Atechocardiography, ejection fraction andleft ventricular diastolic dimension(Ͻ5.6 cm) were within normal limits,whilecardiacindexwasreduced.Nearly50% of patients had left ventricular hy-pertrophy or evidence of concentric re-modeling or hypertrophy (relative wallthickness Ն0.42).16There was Dop-pler evidence of diastolic dysfunctionand elevated left ventricular filling pres-sures with reduced early diastolic me-dial mitral annular tissue velocity (e)and elevated ratio of early to late trans-mitral ventricular filling velocity (E/A),ratio of early transmitral filling veloc-ity to early diastolic medial mitral an-nular tissue velocity (E/e), left atrial vol-ume, and pulmonary artery systolicpressure.Overall, 132 patients (61%) were eli-gible for CMRI, and 117 of these un-derwent CMRI (89%). Ejection frac-tion and left ventricular end-diastolicvolume index were within normal lim-its while cardiac index was reduced. Inthe CMRI cohort, 25% of patients hadleft ventricular hypertrophy. Aortic dis-tensibility was reduced compared withpublished values in older participantswithout heart failure.17Primary End PointAt 24 weeks, the median change in peakoxygen consumption from baseline wasnot significantly different in patientstreated with placebo (Ϫ0.20 [IQR,Ϫ0.70 to 1.00]) and patients treatedwith sildenafil (Ϫ0.20 [IQR, Ϫ1.70 to1.11]), (P=.90) (TABLE 3). Using mul-tiple imputation to account for miss-ing 24-week data, the mean differencebetween sildenafil and placebo was 0.01mL/kg/min (favoring sildenafil, [95%CI, Ϫ0.60 to 0.61], P=.98). Carryingforward 12-week peak oxygen con-sumption when 24-week data weremissing (placebo [n=5] and sildenafil[n=9]), median change in peak oxy-gen consumption (mL/kg/min) frombaseline was Ϫ0.20 (IQR, Ϫ0.83 to1.10) in patients treated with placeboand Ϫ0.13 (IQR, Ϫ1.50 to 1.16) in pa-tients treated with sildenafil (P=.98).In subgroup analyses (eTable 3), thechange in peak oxygen consumptionwas not significantly different be-tween treatment groups when analy-sis was restricted to those patients stilltaking the study drug at week 24, in pa-tients with or without left ventricularhypertrophy by CMRI, with lower orhigher pulmonary artery systolicpressure, with lower or higher NT-Table 2. Baseline Core Laboratory Echocardiographic and Cardiac Magnetic Resonance Imaging Characteristics of the PatientsPlacebo SildenafilAll Patients,Median (IQR)(N=216)No. of Patients(n = 103) Median (IQR)No. of Patients(n = 113) Median (IQR)Doppler echocardiographic dataEjection fraction, % 103 60 (56-65) 110 60 (55-65) 60 (56-65)Cardiac index, L/min/m289 2.48 (2.06-2.86) 86 2.47 (2.09-2.92) 2.47 (2.07-2.92)Left ventricular end-diastolic dimension, cm 76 4.6 (4.3-5.1) 88 4.6 (4.2-5.2) 4.6 (4.2-5.2)Left ventricular mass/BSA, g/m273 77 (63-90) 85 78 (61-97) 77 (62-96)Left ventricular hypertrophy, No. (%) 73 36 (49) 85 40 (47) 76 (48)Relative wall thickness Ն0.42, No. (%) 73 32 (44) 85 43 (51) 75 (48)E/A ratio 70 1.3 (1.0-2.0) 72 1.6 (1.0-2.1) 1.5 (1.0-2.0)Deceleration time, ms 95 190 (156-228) 98 182 (153-212) 185 (155-218)Medial e, m/s 92 0.06 (0.05-0.07) 105 0.06 (0.05-0.08) 0.06 (0.05-0.08)Medial E/e 90 17 (12-24) 98 15 (10-23) 16 (11-23)Left atrial volume index, mL/m274 43 (38-59) 75 44 (33-59) 44 (35-59)Pulmonary artery systolic pressure, mm Hg 75 41 (34-54) 63 41 (32-51) 41 (33-51)CMRI data, median (IQR)Ejection fraction, % 56 66 (59-71) 61 66 (55-70) 66 (58-70)Cardiac index, L/min/m256 2.38 (1.94-2.80) 59 2.32 (2.11-2.74) 2.35 (1.98-2.76)Left ventricular end-diastolic volume/BSA, mL/m256 58 (49-68) 61 53 (46-66) 56 (47-67)Left ventricular mass/BSA, g/m256 61 (53-73) 61 65 (54-78) 63 (54-77)Left ventricular hypertrophy, No. (%) 56 14 (25) 61 16 (26) 30 (26)Aortic distensibility, median (IQR), 10Ϫ3mm Hg-141 1.08 (0.63-1.64) 45 1.18 (0.74-2.07) 1.17 (0.67-1.76)Abbreviations: BSA, body surface area; CMRI, cardiac magnetic resonance imaging; e, early diastolic medial mitral annular tissue velocity; E/A, elevated ratio of early to late trans-mitral ventricular filling velocity; E/e, ratio of early transmitral filling velocity to early diastolic medial mitral annular tissue velocity; IQR, interquartile range.PHOSPHODIESTERASE-5 INHIBITION IN HEART FAILURE©2013 American Medical Association. All rights reserved. JAMA, Published online March 11, 2013 E5Downloaded From: on 03/11/2013
  6. 6. proBNP, with or without atrial fibril-lation or treated or not with renin-angiotensin system antagonists,␤-blockers, or statins.Secondary End Pointsand Safety DataThere were no significant differences inthe clinical rank score, change in 6-min-ute walk distance at 24 weeks, orchange in peak oxygen consumption or6-minute walk distance at 12 weeks be-tween treatment groups (Table 3).There were no significant differences inthe components of the clinical rankscore at 24 weeks or in the overall in-cidence of adverse, or serious adverse,events in the treatment groups.Adverse events occurred in 78 pa-tients (76%) who received placebo and90 patients (80%) who receivedsildenafil. Serious adverse events oc-curred in 16 patients (16%) who re-ceived placebo and 25 patients (22%)who received sildenafil. Adverse eventsoccurring in 5% or more of either studygroup are listed in eTable 4 (available at Patients treatedwith sildenafil had a higher incidence ofvascular adverse events, which in-cluded (but were not limited to) head-ache, flushing, and hypotension, al-though the change in mean arterialpressure from baseline to 24 weeks wasnot significantly different in patientstreated with sildenafil (Ϫ1 [95% CI, Ϫ8to 6]) and patients treated with placebo(Ϫ2 [95% CI, Ϫ10 to 7]), (P=.45). Allseriousadverseeventsexclusiveofdeathor cardiovascular or cardiorenal hospi-talization (Table 3) are listed in eTable5. There were no other notable differ-ences in the incidence of specific seri-ousadverseeventsbetweenstudygroups.Study Drug and Cyclic GuanosineMonophosphate LevelsMedian sildenafil concentrations mea-suredapproximately2hoursafterthelastdose were 78 (IQR, 35-130 ng/mL) at 12weeks and 200 (IQR, 92-330 ng/mL) at24 weeks. At week 24, there was a weakcorrelation between sildenafil dose andsildenafil level (r=0.29, P=.008). Inpaired analysis, plasma cyclic guano-sinemonophosphatelevelsincreasedsig-nificantly from baseline to 24 weeks inpatients randomized to receive sildena-fil (mean increase, 8.72 pmol/mL, [95%CI, 2.56-14.87], P=.006), but not in pa-tients randomized to placebo (mean in-crease, 1.28 pmol/mL, [95% CI, Ϫ6.27to 8.83], P=.74), although the change incyclic guanosine monophosphate wasnotsignificantlydifferentbetweengroups(P=.11).Additional End PointsAt CMRI, there was no difference inchange in left ventricular mass or leftventricular end-diastolic volume indexbetween treatment groups (TABLE 4).There was also no difference in changein Doppler-assessed left ventricular dia-stolic function parameters or pulmo-nary artery systolic pressure betweentreatmentgroups.ByCMRI,arterialelas-tance decreased more and systemic vas-cular resistance tended to decrease morein patients treated with sildenafil(P=.09). However, the change in meanarterial pressure in the entire studypopulation was not significantly differ-ent between groups, as noted above.More patients had missing data for aor-ticdistensibilityat24weeksthanatbase-line, but there was no difference inchange in distensibility between groups.Patients treated with sildenafil had agreaterincreaseincreatinine,cystatinC,NT-proBNP, uric acid, and endothe-lin-1 than patients treated with pla-cebo, whereas changes in aldosteroneand NT-procollagen III were not signifi-cantly different between groups.COMMENTTo our knowledge, the RELAX trial isthe first multicenter study to investi-gate the effect of PDE-5 inhibition inHFPEF. Contrary to our hypothesis,long-term PDE-5 inhibition in HFPEFhad no effect on maximal or submaxi-mal exercise capacity, clinical status,quality of life, left ventricular remod-Table 3. Primary, Secondary, and Safety End PointsPlacebo SildenafilPValueNo. ofPatients VariableNo. ofPatients VariablePrimary end pointChange in peak oxygen consumption at 24 wk, median (IQR), mL/kg/min 94 Ϫ0.20 (Ϫ0.70 to 1.00) 91 Ϫ0.2 (Ϫ1.70 to 1.11) .90Secondary end pointsClinical rank score, meana 94 95.8 95 94.2 .85Change in 6-minute walk distance at 24 wk, median (IQR), m 95 15.0 (Ϫ26.0 to 45.0) 90 5.0 (Ϫ37.0 to 55.0) .92Change in peak oxygen consumption at 12 wk, median (IQR), mL/kg/min 96 0.03 (Ϫ1.10 to 0.67) 97 0.01 (Ϫ1.35 to 1.25) .98Change in 6-minute walk distance at 12 wk, median (IQR), m 96 18.0 (Ϫ14.5 to 48.0) 99 10.0 (Ϫ25.0 to 36.0) .13Components of clinical rank score at 24 wkDeath, No. (%)b 103 0 113 3 (3) .25Hospitalization for cardiovascular or renal cause, No. (%) 103 13 (13) 113 15 (13) .89Change in MLHFQ, median (IQR) 91 Ϫ8 (Ϫ21 to 5) 91 Ϫ8 (Ϫ19 to 0) .44Safety end points, No. (%)Adverse events 103 78 (76) 113 90 (80) .49Serious adverse events 103 16 (16) 113 25 (22) .22Abbreviations: IQR, interquartile range; MLHFQ, Minnesota Living with Heart Failure Questionnaire.aA mean value of 95 in each group is expected under the null hypothesis of no treatment effect.bSite investigator identified causes of death were sudden death (n=1), progressive cardiorenal failure (n=1), and noncardiovascular (n=1).PHOSPHODIESTERASE-5 INHIBITION IN HEART FAILUREE6 JAMA, Published online March 11, 2013 ©2013 American Medical Association. All rights reserved.Downloaded From: on 03/11/2013
  7. 7. eling, diastolic function parameters, orpulmonary artery systolic pressure. Re-nal function worsened more and NT-proBNP, endothelin-1, and uric acidlevels increased more in patients treatedwith sildenafil. Furthermore, there weremore (but not significantly more) pa-tients in the sildenafil group who with-drew consent, died, or were too ill toperform the cardiopulmonary exer-cise test, and patients treated withsildenafil had a higher incidence of vas-cular adverse events. These findings donot suggest that therapy with the PDE-5inhibitor sildenafil provides clinicalbenefit in the general HFPEF popula-tion.Given the strong rationale for test-ing PDE-5 inhibition in HFPEF3and thelack of benefit observed, it is impor-tant to consider whether the studypopulation, specifics of the therapeu-tic intervention, and end points wereappropriate.The clinical characteristics of pa-tients with HFPEF enrolled in major on-going or completed clinical trials havebeen summarized.18The RELAX studypopulationwassimilartoothersintermsof age, sex distribution, and body size.Severity of heart failure in our study wasalso similar to or greater than otherHFPEFtrials,althoughcomorbiditybur-den (diabetes, atrial fibrillation, kidneydisease) may have been greater in thisstudy population. Concentric remodel-ing and hypertrophy were common butnot severe, and Doppler evidence of el-evated filling pressures and pulmonaryhypertension were present as was neu-roendocrine activation consistent withthe heart failure state.However, the characteristics of thestudy population were notably differ-ent from the only other study to ourknowledge that evaluated the effect ofPDE-5 inhibition in HFPEF. In thestudy by Guazzi and coauthors,8sildenafil had a number of beneficial ef-fects as outlined above, although ef-fect on exercise capacity was not tested.Importantly, in that study, patients withHFPEF had fewer comorbidities andsignificantly higher blood pressure, leftventricular mass, and pulmonary ar-tery systolic pressure than the pa-tients in the RELAX study and cath-eterization-documented pulmonaryarterial hypertension, profound rightventricular systolic dysfunction, andright ventricular failure were present.This profile is somewhat atypical forHFPEF cohorts.19It may be that the primary therapeu-tic effects of PDE-5 inhibitors in heartfailure involve the drugs’ ability to di-late the pulmonary vascular bed, en-hance right ventricular contractility,and reduce ventricular interdepen-dence,4,19-22and that pulmonary arte-rial hypertension and right ventricu-lar failure must be significant in orderto observe clinical benefit in HFPEF.Oursubgroupanalysisdidnotshowanytrends toward improvement in peakoxygen consumption in patients withhigher pulmonary artery systolic pres-sure, but the presence of pulmonary ar-terial hypertension or right ventricu-lar dysfunction was not assessed in thisstudy.Although left ventricular hypertro-phy was common in participants in thisstudy, it was far less severe than amongparticipants in the study by Guazzi etal.8In murine-pressure overload stud-ies, PDE-5 inhibition did not have an-Table 4. Additional Prespecified End PointsPlacebo SildenafilPValueNo. ofPatients Median (IQR)No. ofPatients Median (IQR)Change in left ventricular structure by CMRI at 24 wkLeft ventricular mass by CMRI, g 47 0.6 (Ϫ5.7 to 7.9) 49 Ϫ1.5 (Ϫ5.9 to 7.1) .93Left ventricular end-diastolic volume by CMRI, mL 47 Ϫ4.3 (Ϫ15.5 to 8.1) 49 3.7 (Ϫ4.9 to 14.5) .13Change in diastolic function parameters at 24 wkMedial e, m/s 83 0.00 (Ϫ0.01 to 0.01) 77 0.00 (Ϫ0.01 to 0.01) .88E/e 80 Ϫ1.6 (Ϫ4.7 to 2.2) 75 0.2 (Ϫ2.4 to 3.1) .16PA systolic pressure, mm Hg 58 Ϫ2 (Ϫ8 to 8) 45 2 (Ϫ5 to 7) .94Change in vascular function by CMRI at 24 wkArterial elastance, mm Hg/mL 45 0.03 (Ϫ0.14 to 0.23) 47 Ϫ0.08 (Ϫ0.41 to 0.12) .02Systemic vascular resistance, wood units 45 0.13 (Ϫ0.15 to 0.43) 47 Ϫ0.04 (Ϫ0.38 to 0.21) .09Aortic distensibility, 10Ϫ3mm Hg-131 0.13 (Ϫ0.17 to 0.42) 29 0.18 (Ϫ0.12 to 0.67) .38Change in core laboratory biomarkers at 24 wkCreatinine, mg/dL 94 0.01 (Ϫ0.10 to 0.09) 94 0.05 (Ϫ0.04 to 0.15) .047Cystatin C, mg/L 95 0.01 (Ϫ0.08 to 0.11) 95 0.05 (Ϫ0.04 to 0.16) .01NT-proBNP, pg/mL 94 Ϫ23 (Ϫ198 to 139) 95 15 (Ϫ90 to 372) .03Endothelin-1, pg/mL 95 Ϫ0.01 (Ϫ0.48 to 0.47) 95 0.38 (Ϫ0.10 to 0.97) .046Aldosterone, ng/dL 95 0 (Ϫ7.0 to 4.8) 95 Ϫ1.1 (Ϫ7.7 to 3.0) .85NT-procollagen III, ␮g/L 93 Ϫ0.03 (Ϫ1.49 to 1.54) 95 0.07 (Ϫ1.17 to 1.42) .77Uric acid, mg/dL 94 Ϫ0.1 (Ϫ0.7 to 0.7) 94 0.3 (Ϫ0.4 to 1.4) .02Abbreviations: CMRI, cardiac magnetic resonance imaging; e, early diastolic medial mitral annular tissue velocity; E/e, ratio of early transmitral filling velocity to early diastolic medialmitral annular tissue velocity; IQR, interquartile range; NT-proBNP, N-terminal fragment of the precursor to brain-type natriuretic peptide; PA, pulmonary artery.SI conversions: To convert aldosterone from ng/dL to pmol/L, multiply by 27.74; creatinine from mg/dL to ␮mol/L, multiply by 88.4; and uric acid from mg/dL to ␮mol/L, multiplyby 59.485.PHOSPHODIESTERASE-5 INHIBITION IN HEART FAILURE©2013 American Medical Association. All rights reserved. JAMA, Published online March 11, 2013 E7Downloaded From: on 03/11/2013
  8. 8. tihypertrophic effects in mice with lesssevere pressure overload and compen-sated left ventricular hypertrophy withrelatively preserved ejection fraction,whereas dramatic antiremodeling ben-efits were observed in mice with se-vere pressure overload, eccentric leftventricular hypertrophy, reduced ejec-tion fraction, and pulmonary conges-tion.23,24Conceivably, activation ofPDE-5 or of cyclic guanosine mono-phosphate–sensitive downstream path-ways in the left ventricle or other or-gans may occur only in heart failureassociated with advanced left ventricu-lar remodeling.In a randomized clinical trial ofPDE-5 inhibition in pulmonary arte-rial hypertension, the effect of sildena-fil on exercise capacity was not dose re-lated as improvement in 6-minute walkdistance was seen with 20 mg 3 timesdaily after just 4 weeks of therapy withno further improvement with higherdoses or longer duration of therapy.4Sildenafil levels at 12 and 24 weeks werevariable, but on average, similar to ran-dom levels observed with similar dosesamong participants with heart failureand reduced ejection fraction for whomimprovement in exercise capacity withlong-term sildenafil use was observed(Gregory Lewis, MD, MassachusettsGeneral Hospital, written communica-tion, February 2, 2013).5For patients with heart failure and re-duced ejection fraction, the benefit ofPDE-5 inhibition on exercise capacityhas been demonstrated acutely after asingle 50-mg dose,25,26and with 75 mg,3 times daily for 12 weeks (dose upti-trated over the course of 6 weeks).5Al-though only 73% of patients in thesildenafil group attending the 24-week follow-up were taking the per-protocol dose, 92% of patients were tak-ing at least 20 mg 3 times daily. Whilestudies in pulmonary arterial hyper-tension and heart failure and reducedejection fraction have observed effectson exercise capacity with similar dosesand duration of therapy, we cannot ex-clude the possibility that inadequatedose or duration of PDE-5 inhibitioncontributed to our findings.Therapeutic sildenafil levels wereassociated with minimal increases inplasma cyclic guanosine monophos-phate. Heart failure with preservedejection fraction is characterized byendothelial dysfunction27and bylower natriuretic peptide levels thanobserved in heart failure and reducedejection fraction,28which may suggestlimited nitric oxide and natriureticpeptide activity in HFPEF. Inability toenhance cyclic guanosine monophos-phate with PDE-5 inhibition inHFPEF may have contributed to ourfindings.As previously described,3change inpeak oxygen consumption was cho-sen as the primary end point in theRELAX trial based on previous pre-clinical and clinical studies and be-cause noncardiovascular comorbidi-ties and motivational factors caninfluence measures of submaximal ex-ercise performance in HFPEF. Our trialwas powered to detect a clinically sig-nificant difference in the change in peakoxygen consumption between groupsand the estimate of variability (SD, 2.5mL/kg/min) in change in peak oxygenconsumption used in the power calcu-lations was consistent with the stan-dard deviation of change in peak oxy-gen consumption observed in thepatients treated with placebo (2.0 mL/kg/min). The lack of treatment effect onsubmaximal exercise, clinical status,and physiologic end points supports thevalidity of the observed lack of treat-ment effect on maximal exercise ca-pacity.The high prevalence of chrono-tropic incompetence in the study popu-lation is noteworthy. Chronotropic in-competence may contribute to exerciselimitation in HFPEF, and may not beimproved by PDE-5 inhibition.Although numerous studies in ani-mal models of renal dysfunction sug-gest that PDE-5 inhibition amelio-rates progression of renal dysfunctionof various etiologies,3,29-31in this trial,modest but statistically significant wors-ening of renal function was observedin patients treated with sildenafil andwas associated with concordant in-creases in NT-proBNP, uric acid, andendothelin-1, suggesting that the de-cline in renal function was physiologi-cally significant. Studies in pulmo-nary arterial hypertension and erectiledysfunction have not reported wors-ening of renal function with PDE-5 in-hibitor therapy, but little is known ofthe effect of PDE-5 inhibition on renalfunction in HFPEF.There were more (but not signifi-cantly more) patients who withdrewconsent, died, or were too ill to per-form the cardiopulmonary exercise testin the sildenafil treatment group, po-tentially accentuating the lack of ben-efit observed, particularly if those whowithdrew did so due to adverse effectsor poor clinical status.A modest decrease in arterial elas-tance was noted in patients treated withsildenafil in the CMRI cohort. This mayhave been related to an effect ofsildenafil on resistance that tended todecrease more in patients treated withsildenafil, but in the entire cohort, therewere no differences in change in meanarterial pressure between treatmentgroups.The findings of this study must be in-terpreted in the context of other po-tential limitations. Multicenter trialsusing peak oxygen consumption as aprimary end point are challenging, butrigorous methodologies were used inthe design and execution of the exer-cise test study protocol.3Patients wereselected who could perform the test,and who had significant reduction inpeak oxygen consumption—these en-try criteria may have selected for aunique HFPEF phenotype. The trial wasnot powered to address differences inclinical outcomes.CONCLUSIONSAmong patients with HFPEF, PDE-5 in-hibition with administration ofsildenafil for 24 weeks, compared withplacebo, did not result in significant im-provement in exercise capacity or clini-cal status. Continued efforts to iden-tify key pathophysiologic perturbationsand novel therapeutic targets in HFPEFare needed.PHOSPHODIESTERASE-5 INHIBITION IN HEART FAILUREE8 JAMA, Published online March 11, 2013 ©2013 American Medical Association. All rights reserved.Downloaded From: on 03/11/2013
  9. 9. Published Online: March 11, 2013. doi:10.1001/jama.2013.2024Author Affiliations: Department of Medicine, MayoClinic, Rochester, Minnesota (Drs Redfield, Chen,Borlaug, Lin, and Oh); Department of Medicine, Mas-sachusetts General Hospital, Boston (Drs Semigran andLewis); Departments of Biostatistics and Bioinformat-ics (Drs Lee and Anstrom) and Medicine (Drs Velazquezand Hernandez), Statistics (Mr McNulty), and Proj-ect Management (Ms Ibarra), Duke Clinical ResearchInstitute, Durham, North Carolina; Departments ofMedicine (Dr LeWinter) and Pathology and Biochem-istry (Dr Tracy), University of Vermont, Burlington; De-partment of Medicine, University of Montreal andMontreal Heart Institute, Montreal, Canada (Dr Rou-leau); Department of Surgery, University of Utah, SaltLake City (Dr Bull); Department of Medicine, BarnesJewish Hospital, St Louis, Missouri (Dr Mann); De-partment of Medicine, Michael E. DeBakey VA Medi-cal Center and Baylor College of Medicine, Houston,Texas (Dr Deswal); Department of Medicine, Brighamand Women’s Hospital, Boston, Massachusetts (DrsStevenson, Givertz, and Braunwald); Department ofMedicine, Morehouse School of Medicine, Atlanta,Georgia (Dr Ofili); Departments of Medicine (DrsO’Connor, Felker, Patel, and Kim) and Duke Cardio-vascular Magnetic Resonance Center (Dr Kim), DukeUniversity Medical Center and Duke Heart Center, Dur-ham, North Carolina; Department of Medicine, Hen-nepin County Medical Center, Minneapolis, Minne-sota (Drs Goldsmith and Bart); and Division ofCardiovascular Sciences, National Heart, Lung, andBlood Institute, Bethesda, Maryland (Dr Mascette).For a complete listing of the RELAX site representa-tives see the online supplement at Contributions: Drs Lee and Anstrom had fullaccess to all the data in the study and take responsi-bility for the integrity of the data and the accuracy ofthe data analysis.Study concept and design: Chen, Semigran, Lee,LeWinter, Rouleau, Bull, Deswal, Stevenson, O’Connor,Felker, Goldsmith, Bart, McNulty, Velazquez,Hernandez, Braunwald, Redfield.Acquisition of data: Chen, Borlaug, Semigran, Lee,Lewis, LeWinter, Rouleau, Bull, Deswal, Stevenson,Givertz, Ofili, O’Connor, Felker, Bart, McNulty, Ibarra,Lin, Patel, Kim, Tracy, Velazquez, Hernandez, Redfield.Analysis and interpretation of data: Borlaug, Semigran,Lee, Lewis, LeWinter, Bull, Mann, Deswal, Givertz,Felker, McNulty, Ibarra, Lin, Oh, Patel, Kim, Tracy,Velazquez, Anstrom, Hernandez, Mascette, Braunwald,Redfield.Drafting of the manuscript: Chen, Borlaug, LeWinter,Bull, O’Connor, McNulty, Velazquez, Redfield.Critical revision of the manuscript for important in-tellectual content: All authors.Statistical analysis: Lee, Bull, McNulty, Velazquez,Anstrom.Obtained funding: Chen, Semigran, Lee, Bull, Deswal,Ofili, Felker, McNulty, Velazquez, Hernandez,Mascette, Redfield.Administrative, technical, or material support: Chen,Borlaug, Lee, Rouleau, Bull, O’Connor, McNulty, Ibarra,Oh, Kim, Tracy, Velazquez, Hernandez, Mascette,Braunwald.Study supervision: Borlaug, Lewis, Deswal, Givertz,O’Connor, Felker, Goldsmith, Bart, McNulty, Kim,Velazquez, Mascette, Braunwald, Redfield.Conflict of Interest Disclosures: All authors have com-pleted and submitted the ICMJE Form for Disclosureof Potential Conflicts of Interest. Dr Redfield re-ported receiving financial support from the NationalInstitutes of Health (NIH) and royalties from An-nexon. Dr Chen reported receiving funding for pat-ents that his institution has licensed to Nile Therapeu-tics and Annexon with other patents pending at theUS Patent and Trademark Office. He also reported thathe has royalties with Nile Therapeutics, Annexon, andUp To Date. Dr Borlaug reported receiving consult-ing fees from Medscape, Amgen, and GlaxoSmithKlineand receiving financial support from Atcor Medical andGilead. Dr Semigran reported receiving financial sup-port from the NIH for participation in the Heart Fail-ure Network and from Bayer. Dr Lee reported receiv-ing financial support from the NIH for participationin the Heart Failure Network. Dr LeWinter reportedreceiving financial support from the NIH for partici-pation in the Heart Failure Network. Dr Bull reportedreceiving financial support from the NIH for partici-pation in the Heart Failure Network. Dr Deswal re-ported receiving financial support from the NIH forparticipation in the Heart Failure Network. Dr Steven-son reported receiving financial support from the NIHfor participation in the Heart Failure Network. Dr Gi-vertz reported receiving financial support from the NIHfor participation in the Heart Failure Network. Dr Ofilireported receiving financial support from the NIH, re-ceiving consulting fees from Merck, Novartis, and Ar-bor Pharmaceuticals and lecture fees from Arbor Phar-maceuticals. She is currently employed by theMorehouse School of Medicine and has grants pend-ing from the National Heart, Lung, and Blood Insti-tute and National Institute on Minority Health andHealth Disparities. Dr O’Connor reported receiving con-sulting fees from Roche Diagnostics, Amgen, Novar-tis, Ikaria, Acetlion Pharma, Heartware, ResMed, Pozen,GE Healthcare, Johnson & Johnson, Gilead, Critical Di-agnostics, BG Medicine, Otsuka, Astellas, Novella, Cy-tokinetics, and Capricor; holding stock options withNeurotronik/Interventional Autonomics Corpora-tion; editing American College of Cardiology; and co-owning Cardiology Consulting Associates. Dr Felkerreported receiving financial support from the NIH; con-sulting fees from Novartis, Amgen, Trevena, RocheDiagnostics, Merck, Singulex, and BG Medicine; andfunding from Amgen, Otsuka, and Roche Diagnos-tics. Dr Bart reported receiving financial support fromthe NIH for participation in the Heart Failure Net-work. Ms Ibarra reported receiving financial supportfrom the NIH for participation in the Heart Failure Net-work. Dr Oh received financial support from the NIHfor the Echo Core Lab. Dr Patel has received consult-ing fees from Genzyme, Baxter, Jensen, and Bayer, andhis financial institution receives financial support fromAstraZeneca, Johnson & Johnson, and Maquet. Dr Kimreported receiving financial support from the NIH asthe Heart Failure Network Data Coordinating Centerand MRI Core Lab, and funding for a patent withNorthwestern University. His institution has receiveda grant from Siemens. Dr Tracy reported receiving fi-nancial support from the NIH for participation in theHeart Failure Network, and consulting fees from Merck,Tibotec—Johnson & Johnson, and Abbott. He has alsogiven expert testimony about biomarkers in blood clot-ting and is the owner of Haematologic Technologies.Dr Velazquez reported receiving financial support fromthe NIH for participation in the Heart Failure Net-work. Dr Anstrom reported receiving financial sup-port from the NIH for participation in the Heart Fail-ure Network. Dr Hernandez reported receiving financialsupport from the NIH for participation in the HeartFailure Network and consulting fees from AstraZen-eca, Corthera, Janseen, and Bristol-Myers Squibb. Hisinstitution has received funding from Amylin, John-son & Johnson, and Bristol-Myers Squibb. Dr Braun-wald reported receiving consulting fees from Merck,Daiichi Sankyo, Genzyme, Amorcyte, Medicines Co,MC Communications, Ikaria, CardioRentis, sanofi-aventis; funding (or pending funding) from AstraZen-eca, Johnson & Johnson, Merck, sanofi-aventis, Dai-ichi Sankyo, GlaxoSmithKline, Bristol-Myers Squibb,Beckman Coulter, Roche Diagnostics, and Pfizer; com-pensation for lectures for Eli Lilly, Merck, CVRx (nocompensation), CV Therapeutics (now Gilead), Dai-ichi Sankyo, MC Communications, Manarini Interna-tional, Medscape, and Bayer; and payment for devel-opment of educational presentations from MCCommunications. No other disclosures were re-ported.Funding/Support: This work was supported by grantsU10HL084904 (for the data coordinating center), andU10HL084861, U10HL084875, U10HL084877,U10HL084889, U10HL084890, U10HL084891,U10HL084899, U10HL084907, and U10HL084931(for the clinical centers) from the National Heart, Lung,and Blood Institute. This work is also supported by grantUL1TR000454 from the National Center for Advanc-ing Translational Sciences and grant 8 U54 MD007588from the National Institute on Minority Health andHealth Disparities. Pfizer provided study drug (sildenafiland matched placebo).Role of the Sponsor: Pfizer had no role in the designand conduct of the study, collection, management,analysis, or interpretation of the data, or preparation,review, or approval of the manuscript. National Heart,Lung, and Blood Institute representatives provided ad-vice on the trial design and appointed the protocolreview committee and data and safety monitoringboard.Disclaimer: The authors are solely responsible for thecontent of this article, which does not necessarily rep-resent the official views of the National Heart, Lung,and Blood Institute or the National Institutes of Health.Online-Only Material: The eMethods, eReferences,eTables 1 through 5, and eAppendices are availableat Contributions: We thank the patients whoparticipated in this study, the Heart Failure Networksite investigators and coordinators, the members ofthe Heart Failure Network data and safety monitor-ing board and protocol review committee, and the Na-tional Heart, Lung, and Blood Institute representa-tives. For a complete listing of the Heart FailureNetwork members, see Appendix C available at Owan TE, Redfield MM. Epidemiology of dia-stolic heart failure. Prog Cardiovasc Dis. 2005;47(5):320-332.2. Shah RV, Desai AS, Givertz MM. The effect of renin-angiotensin system inhibitors on mortality andheart failure hospitalization in patients with heart fail-ure and preserved ejection fraction: a systematic re-view and meta-analysis. J Card Fail. 2010;16(3):260-267.3. Redfield MM, Borlaug BA, Lewis GD, et al; HeartFailure Clinical Research Network. PhosphdiesteRasE-5inhibition to improve clinical status and exercise ca-pacity in diastolic heart failure (RELAX) trial: rationaleand design. Circ Heart Fail. 2012;5(5):653-659.4. Galiè N, Ghofrani HA, Torbicki A, et al; SildenafilUse in Pulmonary Arterial Hypertension (SUPER) StudyGroup. Sildenafil citrate therapy for pulmonary arte-rial hypertension. N Engl J Med. 2005;353(20):2148-2157.5. Lewis GD, Shah R, Shahzad K, et al. Sildenafil im-proves exercise capacity and quality of life in patientswith systolic heart failure and secondary pulmonaryhypertension. Circulation. 2007;116(14):1555-1562.6. Guazzi M, Vicenzi M, Arena R. Phosphodiester-ase 5 inhibition with sildenafil reverses exercise oscil-latory breathing in chronic heart failure: a long-termcardiopulmonary exercise testing placebo-controlledstudy. Eur J Heart Fail. 2012;14(1):82-90.7. Guazzi M, Vicenzi M, Arena R, Guazzi MD. PDE5inhibition with sildenafil improves left ventricular dia-stolic function, cardiac geometry, and clinical statusin patients with stable systolic heart failure: resultsof a 1-year, prospective, randomized, placebo-controlled study. Circ Heart Fail. 2011;4(1):8-17.PHOSPHODIESTERASE-5 INHIBITION IN HEART FAILURE©2013 American Medical Association. All rights reserved. JAMA, Published online March 11, 2013 E9Downloaded From: on 03/11/2013
  10. 10. 8. Guazzi M, Vicenzi M, Arena R, Guazzi MD. Pul-monary hypertension in heart failure with preservedejection fraction: a target of phosphodiesterase-5 in-hibition in a 1-year study. Circulation. 2011;124(2):164-174.9. Fletcher GF, Balady G, Froelicher VF, Hartley LH,Haskell WL, Pollock ML; Writing Group. Exercise stan-dards: a statement for healthcare professionals fromthe American Heart Association. Circulation. 1995;91(2):580-615.10. Packer M. Proposal for a new clinical end pointto evaluate the efficacy of drugs and devices in thetreatment of chronic heart failure. J Card Fail. 2001;7(2):176-182.11. Enright PL, Sherrill DL. Reference equations forthe six-minute walk in healthy adults. Am J Respir CritCare Med. 1998;158(5 Pt 1):1384-1387.12. Khan MN, Pothier CE, Lauer MS. Chronotropic in-competenceasapredictorofdeathamongpatientswithnormalelectrogramstakingbetablockers(metoprololoratenolol). Am J Cardiol. 2005;96(9):1328-1333.13. Chirinos JA, Segers P, De Buyzere ML, et al. Leftventricular mass: allometric scaling, normative val-ues, effect of obesity, and prognostic performance.Hypertension. 2010;56(1):91-98.14. Feldman AM, Silver MA, Francis GS, et al; PEECHInvestigators. Enhanced external counterpulsation im-proves exercise tolerance in patients with chronic heartfailure. J Am Coll Cardiol. 2006;48(6):1198-1205.15. Abraham WT, Fisher WG, Smith AL, et al;MIRACLE Study Group, Multicenter InSync Random-ized Clinical Evaluation. Cardiac resynchronization inchronic heart failure. N Engl J Med. 2002;346(24):1845-1853.16. Lang RM, Bierig M, Devereux RB, et al; Cham-ber Quantification Writing Group; American Societyof Echocardiography’s Guidelines and StandardsCommittee; European Association of Echocardiography.Recommendations for chamber quantification: a re-port from the American Society of Echocardio-graphy’s Guidelines and Standards Committee and theChamber Quantification Writing Group, developed inconjunction with the European Association of Echo-cardiography, a branch of the European Society ofCardiology. J Am Soc Echocardiogr. 2005;18(12):1440-1463.17. Hundley WG, Kitzman DW, Morgan TM, et al.Cardiac cycle-dependent changes in aortic area anddistensibility are reduced in older patients with iso-lated diastolic heart failure and correlate with exer-cise intolerance. J Am Coll Cardiol. 2001;38(3):796-802.18. Shah SJ, Heitner JF, Sweitzer NK, et al. Baselinecharacteristics of patients in the Treatment of Pre-served Cardiac Function Heart Failure with an Aldo-sterone Antagonist (TOPCAT) trial. Circ Heart Fail.2012.19. Forfia PR, Borlaug BA. Letter by Forfia and Bor-laug regarding article, “Pulmonary hypertension inheart failure with preserved ejection fraction: a tar-get of phosphodiesterase-5 inhibition in a 1-yearstudy.” Circulation. 2012;125(8):e408-e410.doi:10.1161/CIRCULATIONAHA.111.064584.20. Nagendran J, Archer SL, Soliman D, et al. Phos-phodiesterase type 5 is highly expressed in the hy-pertrophied human right ventricle, and acute inhibi-tion of phosphodiesterase type 5 improves contractility.Circulation. 2007;116(3):238-248.21. Xie YP, Chen B, Sanders P, et al. Sildenafil pre-vents and reverses transverse-tubule remodeling andCa(2ϩ) handling dysfunction in right ventricle failureinduced by pulmonary artery hypertension.Hypertension. 2012;59(2):355-362.22. Borgdorff MA, Bartelds B, Dickinson MG, et al.Sildenafil enhances systolic adaptation, but does notprevent diastolic dysfunction, in the pressure-loadedright ventricle. Eur J Heart Fail. 2012;14(9):1067-1074.23. Nagayama T, Hsu S, Zhang M, et al. Pressure-overload magnitude-dependence of the anti-hypertrophic efficacy of PDE5A inhibition. J Mol CellCardiol. 2009;46(4):560-567.24. Takimoto E, Champion HC, Li M, et al. Chronicinhibition of cyclic GMP phosphodiesterase 5A pre-vents and reverses cardiac hypertrophy. Nat Med.2005;11(2):214-222.25. Lewis GD, Lachmann J, Camuso J, et al. Sildena-fil improves exercise hemodynamics and oxygen up-take in patients with systolic heart failure. Circulation.2007;115(1):59-66.26. Guazzi M, Tumminello G, Di Marco F, FiorentiniC, Guazzi MD. The effects of phosphodiesterase-5 in-hibition with sildenafil on pulmonary hemodynamicsand diffusion capacity, exercise ventilatory effi-ciency, and oxygen uptake kinetics in chronicheart failure. J Am Coll Cardiol. 2004;44(12):2339-2348.27. Borlaug BA, Olson TP, Lam CS, et al. Global car-diovascular reserve dysfunction in heart failure withpreserved ejection fraction. J Am Coll Cardiol. 2010;56(11):845-854.28. Bishu K, Deswal A, Chen HH, et al. Biomarkersin acutely decompensated heart failure with pre-served or reduced ejection fraction. Am Heart J. 2012;164(5):763-770 e763.29. Tapia E, Sanchez-Lozada LG, Soto V, et al. Sildenafiltreatment prevents glomerular hypertension and hy-perfiltration in rats with renal ablation. Kidney BloodPress Res. 2012;35(4):273-280.30. Medeiros PJ, Villarim Neto A, Lima FP, AzevedoIM, Lea˜o LR, Medeiros AC. Effect of sildenafil in re-nal ischemia/reperfusion injury in rats. Acta Cir Bras.2010;25(6):490-495.31. Choi DE, Jeong JY, Lim BJ, et al. Pretreatment ofsildenafil attenuates ischemia-reperfusion renal in-jury in rats. Am J Physiol Renal Physiol. 2009;297(2):F362-F370.PHOSPHODIESTERASE-5 INHIBITION IN HEART FAILUREE10 JAMA, Published online March 11, 2013 ©2013 American Medical Association. All rights reserved.Downloaded From: on 03/11/2013