good afternoon i'm Chris Okconor uh professor of medicine at uh Duke University and we're here at the Duke Clinical Research Institute with Dr david Whan and we're here to discuss the results of the HF action trial david great to have you here well thanks Chris we uh did a a major study of exercise training in heart failure over the past seven years and the results were recently presented at the AHA and we're going to have David Whan who is associate professor of medicine at the Jefferson Medical College give us the results david thanks so uh today I'm going to present the primary results of the HF action study this was the study looking at the efficacy and safety of exercise training as a treatment modality in patients with chronic heart failure uh these are the disclosures for both Dr myself and Dr okconor and I'm making this presentation on behalf of the HF action investigators and study coordinators at the 82 participating centers across the United States Canada and France as you can see Dr oconor was the chair of our executive committee and Dr ilana Pina at Case Western Reserve was the uh chairwoman for the steering committee this slide uh explains the background as you can see uh exercise training has been evaluated in heart failure patients for approximately 20 years there were several studies that have demonstrated an exercise uh training benefit in terms of functional capacity uh with heart failure in these studies there was an increase in not only exercise capacity but also quality of life and improvement in biomarkers when a number of studies were combined in a meta analysis as shown here on this slide exercise training was found to improve um all cause mortality as can be seen at the bottom this resulted in a reduction of 39% in the uh hazard ratio which was uh close to significance but it's important to remember that there are some limitations to these prior studies they were relatively small and the majority of them were performed at single centers and because of these issues most of them were underpowered to evaluate mortality and morbidity in addition there was a lack of adequate control groups and limited safety data that came from the studies because of these limitations and the need to uh evaluate exercise training in a larger cohort the HF action study was uh designed and implemented the primary hypothesis for HF action is that patients with left ventricular systolic dysfunction and New York Heart Association class 2 through four symptoms who undergo exercise training in addition to usual care will have 20% lower rate of all-c cause mortality or all-c cause hospitalization which is the primary endpoint for the study over two years than patients who receive usual care alone in addition to the primary endpoint we had a number of other secondary endpoints including cardiovascular mortality and cardiovascular hospitalization cardiovascular mortality and heart failure hospitalization mortality safety exercise capacity all of which will be discussed here quality of life which Dr flynn will be discussing shortly and cost the HF action study design uh is shown here on this slide we enrolled uh identified patients with chronic heart failure New York heart association class 2 through four symptoms left ventricular ejection fraction less than or equal to 35% we asked that patients be on optimal heart failure medical therapy and were capable of exercise the exclusion criteria included uh uh not having any uh cardiovascular event within six weeks of randomization the ability to exercise safely uh as will be tested uh in an exercise uh test and um uh no uh active training by the heart failure patient prior to randomization as uh discussed they patients underwent a cardopulinary exercise test in order to evaluate the safety of training and an echo cardiogram patients were then randomized in a one-to-one fashion to either usual care or exercise training the randomization was stratified by center and heart failure ideology the median follow-up for patients in the HF action study were 2.5 years the usual care patients received optimal medical therapy in addition they received education regarding their heart failure condition this education also included uh recommendation of 30 minutes of physical activity this was based on the ACCA and European Society of Cardiology guidelines in order to balance the interaction between the patients in the usual care group and the exercise training group patients receive phone calls every two weeks for the first nine months and then every month from months 10 through 24 followup in the exercise training arm patients receive the same type of care as a usual as uh patients in the usual care arm but in addition they received supervised training this consisted of 36 supervised sessions approximately 30 minutes uh three times a week at an exercise intensity of 70% heart rate reserve during supervised training and at the and afterwards uh patients were asked to exercise at home we provided exercise equipment uh for the patients as well as heart rate monitors and the uh request to the patient was for them to exercise approximately five times per week 40 minutes a day uh at an intensity of 70% heart rate reserve uh this slide shows the study organization as you can see this was a complex study which involved the National Heart Lung and Blood Institute the executive committee and the steering committee as well as a coordinating center here at the Duke Clinical Research Institute we also had core labs for CPX studies echo cardiogram and adherence and exercise training intensity centers across the country as well as in Canada and France as described before enrolled patients at multiple sites in addition there was an independent data safety monitoring board the HF action study was designed to provide 90% power to detect a 20% reduction over two years if patients were compliant with the exercise intervention there were a number of assumptions that were used in uh developing the sample size first the annual event rate was assumed to be 30% in the usual care group non-adherence rates of 30% in the first year of follow-up and 12.5% annually thereafter were also assumed we expected an annual crossover rate of 5% from the usual care arm to exercise training and we had a planned median follow-up of 2.5 years to account for non-adherence in crossover the study was actually powered to detect 11% reduction in the primary endpoint the analysis was a two-sided uh analysis with an alpha of 0.05 initially our target sample size was 3,000 patients however in discussions with the DSMBB when we were uh notified about the actual event rate for the total cohort the total sample size was reduced to 2300 um based on this uh higher event rate the analysis was an intent in attention to treat analysis uh treatments were compared using a time toevent based on the log rank test and stratified by heart failure ideology relative risks were derived from the Cox proportional hazard model and reported as hazard ratios with 95% confidence intervals prespecified in our protocol was an adjusted analysis adjustments were made for highly prognostic factors that may improve the accuracy of the estimated treatment effect these were uh determined independent of uh randomization the strongest prognostic factors for the primary endpoint selected without using the treatment information were CPX duration left ventricular ejection fraction Beck depression inventory and history of atrial fibrillation and flutter the adjusted analysis included these four variables as well as heart failure ideology and will be presented along with the unadjusted analysis this slide uh shows our baseline characteristics for the group as you can see the mean median age was 59 we were able to enroll approximately 30% female and 30% African-American the median left ventricular ejection fraction was 25% and the peak V2 in both arms was approximately 14.4 milliliters per minute per kilogram as you can see in this slide our centers and investigators did an excellent job in having patients on optimal medical therapy at the time of enrollment uh subjects in the HF action study uh were on high uh uh ACE inhibitor and or an andotensin receptor blocker approximately 92% of the time beta blocker use was at 95% of time aldoststerone antagonism uh use was at 43% ICD use at 40% this slide uh represents the uh actual exercise training that occurred within the exercise training cohort the slide is divided into two sections the first section which is the first red line is the exercise training intensity during supervised training the red lines represent the goals during both the supervised training uh uh time point which is in months one through three and then the home or maintenance exercise training program during the supervised training program the uh uh goal was 90 minutes uh per week it increased to 120 minutes per week in the subsequent months as you can see adherence was uh was good but not meeting target for the median which is represented by the dots and over time the exercise training slowly reduced in terms of the groups so that at three years approximately 50% of the uh subjects were exercising at or above um 50 minutes per week when we look at how many patients were exercising at the goal or above approximately 30% of the subjects uh were exercising at this intensity this study represents the changes that we saw in terms of uh six-minute walk and cardiopulmonary exercise tests or the functional status of the uh patients as you can see here the median change in six-minute walk from baseline to 3 months uh did increase significantly for the exercise training uh arm compared to the usual care for 6-minute walk CPX duration and peak V2 it is important to recognize that we had assumed a slightly larger uh change in C and peak V2 uh but these still were significant at 12 months the 6-minute walk difference between exercise training arm and usual care arm was not significant approximately 12 or 13 uh meters of uh improvement cpx exercise duration did increase and peak V2 also increased to significant levels in the exercise training group compared to the usual care arm this slide represents the primary outcome for the HF action study of all cause mortality or all-c cause hospitalization as you can see patients in uh randomized to the exercise training arm had a modest improvement in this endpoint with a hazard ratio of 93 in the primary analysis this was not significant however in the adjusted analysis the hazard ratio uh reduced to 89 or 11% reduction and this was significant at 03 this slide represents the secondary outcome of cardiovascular mortality or cardiovascular hospitalization uh again you see we see a modest improvement in this endpoint with a hazard ratio of 0.92 the adjusted uh hazard ratio of 0.91 neither of these reach a significant um uh reach significance and this slide represents cardiovascular mortality or heart failure hospitalization in this uh uh for this endpoint we saw a more uh significant uh decrease in the uh uh endpoint for patients in the exercise training arm in the unadjusted analysis uh the hazard ratio was 087 which was uh very close to significant at 06 the adjusted hazard ratio of 085 did reach significant at 03 and finally for all cause mortality uh there was no significant difference between either group as shown on this slide when we looked at subgroup analysis uh there was a consistent trend uh among the different subgroups that we evaluated including age sex ideology baseline ejection fraction uh history of myioardial function or uh being on an ACE inhibitor uh the p value for interactions were non-significant so again uh very consistent modest improvement in the uh endpoint this is for the primary endpoint we did track serious adverse events of uh patients uh participating in the HF action study um as you can see here there were at least uh one cardiovascular event in approximately 40% of the usual care arm and 37% of the exercise training arm um ICD firing occurred at least once uh in approximately 20% of the uh uh both cohorts patients we uh were tracked to see if they were hospitalized after physical activity as you can see here a very low percentage of patients uh both in the usual care arm and exercise training arm were uh admitted for this uh subjects admitted for fracture of the hip or pelvis were shown here also very low and then uh uh deaths that were uh identified as possibly occurring within three hours of physical activity also uh very low it's important to recognize that uh the HF accident study had uh some limitations uh two of which are recognized here first um suboptimal adherence in the exercise training group which was shown on the previous slide and physical activity by the usual care group may have diminished the benefit of exercise training we are currently undergoing an analysis to look at this um factor to see if we can uh detect the benefit of exercise training when adherence is accounted for in addition um in a study of this nature where we're uh evaluating a lifestyle intervention blinding of subjects and research personnel is just not possible um however it's worth pointing out that core labs that participated in HF action uh were blinded to u uh enrollment uh for the subjects and in addition the clinical endpoint committee uh was blinded uh to uh randomization so in conclusion HF action is the largest randomized trial of exercise training in patients uh with heart failure uh we did show that regular exercise training is safe in patients with heart failure exercise training provided a modest improvement in the physiologic endpoints of six-minute walk and CPX duration and peak V2 furthermore uh based on the main analysis adjusted for heart failure ideology alone exercise training produced a modest non-significant decrease in the primary endpoint all cause mortality or all cause hospitalization and key secondary clinical endpoints in the protocol specified analysis adjusted for the prognostic factors uh listed before the treatment effect was statist statistically significant for the primary endpoint and for the secondary endpoint of cardiovascular mortality or heart failure hospitalization based on the safety of exercise training and the modest reduction in clinical events the HF action study results support prescribed exercise training program for patients with reduced LV function and heart failure symptoms in addition to evidence-based therapy thank you David congratulations on just a fantastic trial to the study coordinators the investigators the cardiac rehab personnel just a remarkable achievement to conduct this trial could you contrast what it takes to do a trial of behavioral intervention versus a trial of a drug or a device yeah i mean as you're pointing out in a lifestyle intervention where subjects are approached to participate um and usually they're um tend to be inclined to uh exercise or diet or any type of lifestyle intervention there are a number of issues that come into play um one is uh patients who don't get randomized in terms of usual care you have are dealing with crossover they know what they're getting um and you know in a drug study with blinding with placebo that's really not possible um in addition it's very hard as we all know to maintain a lifestyle intervention so subjects as we saw in the HF action study um have a hard time consistently uh taking their drug so to speak um if you contrast this to a surgical intervention um it's very clear when you get your intervention and once it's done it's done um so in thinking about the clinical study we had to spend a lot of time in dealing with adherence and promoting exercise we had to provide a number of uh um resources to both the investigators and the study coordinators as well as to the patients to maintain exercise i mean we we delivered uh exercise equipment to every patient in the exercise training arm um and our coordinators uh were able to find people to set those that equipment up for these patients who really are debilitated by their disease well this was a trial that many uh experts across the world said couldn't be done first of all as you've pointed out the the dogma in and recommendation of uh physical activity for many years had been you know bed rest particularly in the sicker patients the class 3 fours don't move too much take it easy so we had to overcome that sort of intellectual barrier and then um we had all these small trials sort of showing this benefit so that it began to creep into the guidelines already and so there were there were a number of uh sort of obstacles out there in the in the field and um I guess it would be uh fair to say that um this is the type of trial that probably could never be replicated again yeah I think it would be difficult and I think we've learned a lot of lessons in terms of implementing exercise training in a population uh of uh patients um but I I do think it sets a standard as you're pointing out that I I think uh as we get involved in research and we do the single centers and we see signals that suggest a benefit we have to caution ourselves not to jump ahead and uh and mandate that whatever that intervention in is is going to be beneficial for patients you know I'm thinking of the HERS study in terms of hormone replacement for women as a a wonderful example where initial studies showed this uh signal but when it was truly evaluated in a study uh that was appropriate it it really did not have a benefit and in fact it may have harmed uh women so I I think in in the same way with exercise there was a signal there but I I the um really the uh accommodation to the NIH and and saying that it was necessary to do the study even though it was in the guidelines as I mentioned the education um it was this is the type of thing that needs to be done in research is to validate the single single center studies the early studies safety was a big concern at the beginning of the trial we put in all kinds of effort to make sure that we weren't going to um put patients at undue risk from this fairly uh uh intensive exercise training 200 minutes a week at heart rate reserves of 60 to 70% were you surprised by the safety data um I think if you asked me that question at the beginning I would say yes because I didn't know about the um uh two factors one was the excellent uh medication use so I think that helped us in terms of safety that the patients were on optimal therapy they had um they were uh protected and I also think uh when we implemented our adherence intervention and really were staying on top of patients I mean that was providing a level of care that's probably a little different than what heart failure uh patients receive in the community um but you know overall I was surprised that there wasn't any difference i was happy to see that i think it's nice to show uh both uh our patients as well as other providers that recommending exercise training is going to be safe um the real question will be can your patient actually do the uh training regimen and uh you know we'll have more information about adherence and its effect on outcomes well let's talk a little bit about the efficacy um obviously we were a little maybe uh um surprised that there wasn't a bigger signal based on the meta analysis you showed about a 30% um relative risk reduction um we didn't see that in the primary or the important secondaries why do you think what do you think the key three factors were that we didn't see a bigger signal well um I think we've talked about uh some of them one obviously is adherence um so and and I'll also put crossover with that so you know when you're trying to detect a difference in a treatment you it's important to maintain that treatment and the difference between your usual care or control arm and your intervention arm um I think the second which we also mentioned was the um high use of optimal medical therapy in the guideline uh basis as well as the level of care um I think the other uh issue here is and it kind of goes along with that second is just the natural trends within heart failure population i I think what we're beginning to see is that in clinical trials at least so you know they tend to be the younger uh patients who are randomized into them uh the event rates are falling a little bit and that you know I say that on the one hand particularly for mortality I don't I don't think we saw any signal at all in mortality where I thought we would see a signal at least some uh uh difference maybe not significant now clearly we had more events than expected and I think that has to do with uh the fact that heart failure patients have a lot of uh other types of events other than heart failure last question David and a tough one i think uh let's see if you you're up for it the um uh I think the the world as we know has has seen the these results and uh struggle somewhat with the issue of the adjusted analysis that you showed the you had the main analysis and the adjusted analysis tell us a little bit how the uh general uh health care provider the general um uh study coordinator or clinician out there uh should interpret the adjusted analysis as in contrast to the main analysis yeah I kind of see this as um contrasting u the regulations and um kind of the expectations for drug trials that companies are bringing forth to the FDA for approval where those studies are um vetted by the FDA they're the expectation is that you're going to use your primary analysis and and that's the way it goes and if you don't meet your primary then you're going to go back and redesign another study maybe to differentiate your cohort and the reality is for exercise training this is not going to the FDA um and and we're not going to be able to go back and reconfigure another study and so it's very important to recognize that the adjusted analysis which was has been used in many studies is a way of really comparing the similar patients among the two cohorts um typically when you randomize that doesn't that takes care of those differences but in cases like an HF action there were subtle differences and along the um identified prognostic indicators they all went kind of against exercise training so that when we adjusted for them we began to see this difference that really was significant it's also important to realize that the point estimate was going in the right direction in both the primary analysis and the secondary of cardiovascular mortality and heart failure hospitalization it just went a little bit further when you made the adjustment so I think what we can say in looking at HF action was that there's a modest improvement it wasn't as great as what we had initially thought um but it that's not surprising knowing that it was based on single centers and meta analyses um but it is an improvement and I think we can feel comfortable in advising our patients with heart failure that exercise training is safe and that it can benefit them not only in terms of these clinical endpoints but also in terms of their functional capacity the physiologic endpoints that we saw and as you'll hear uh in a short time about quality of life so it's kind of like uh a race where the exercise training group um and the usual care group really weren't at the same starting line it may have been like the exercise training group was a couple steps behind the starting line and that was the sort of the main analysis and then when you do the adjusted for the you know correcting for something important you level it and uh you see the maybe a truer signal right of the uh treatment effect and the important thing in using that analogy is that in both cases the patients in the subjects in exercise training crossed the finish line first right and that in the adjustment they just crossed it a little bit faster faster so well David thank you for joining us in the uh DCRI studio here in Durham North Carolina we've heard the results of the HF Action clinical main results and we'll shortly be hearing the quality of life results david's got to do some additional work here and then catch a plane but David thank you for joining us today great thank you