Negative Adaptive CRT Trial Yields Useful Clinical Messages

Daniel M. Keller, PhD

April 18, 2023

Post hoc analysis of the AdaptResponse global randomized trial suggests the value of adaptive vs conventional cardiac resynchronization therapy (CRT) in patients with symptomatic heart failure (HF), left bundle branch block (LBBB), and intact conduction to the right ventricle.

The study tested the hypothesis that pacing only the left ventricle (LV) would be superior to biventricular pacing. However, because the trial was stopped for futility at an interim analysis, the overall result was that it was a negative trial, but it still has yielded some instructive information.

Presenting the study at a Late Breaking Science session at the 2023 European Heart Rhythm Association congress in Barcelona, Bruce Wilkoff, MD, Cleveland Clinic Foundation, Cleveland, Ohio, described the method as "fusing the right ventricular intrinsic conduction and left ventricular stimulation." Thus, enrolled patients had intact right ventricular conduction with left bundle branch block.

By timing LV activation to intrinsic right ventricular (RV) activity, "It probably gives you the most rapid activation of the heart, but also makes the whole system more efficient…by both taking the right population and leveraging what the heart can give to us and give us the optimal way of activating the heart," Wilkoff said. "Once a minute, it remeasures exactly the right moment to pace the left side to fuse perfectly with the right side."

The study randomized patients with intact atrioventricular conduction and LBBB 1:1 either to adaptive CRT (n = 1810) or to standard CRT (n = 1807) using the same device with the capability to turn the adaptive mode on or off.

Patients were enrolled in the trial between January 2014 and August 2019 and followed for a median of 59 months. Patient groups were well matched at baseline for age, gender (43% female), electrocardiographic measures (PR interval approximately 172 msec), and LV ejection fraction (approximately 25.5%), and for left bundle branch block by Strauss criteria (approximately 96%).

About half were in New York Heart Association (NYHA) class III/IV. They were also well matched according to their drug therapies, with fewer than 1% on sodium-glucose cotransporter 2 (SGLT2) inhibitors. Wilkoff noted that "the proportion of female patients was higher than in any other trial of heart failure with reduced ejection fraction."

Missed Endpoint, With a Twist

This single-blind, multinational trial randomized 3716 patients to adaptive or conventional CRT (3617 analyzed) to have 90% power to show an 18% reduction in the primary composite endpoint of death from any cause or intervention for HF decompensation, using blinded endpoint adjudication.

At the third interim analysis in May 2022, almost 8 years after the first enrollment in the trial, fewer patients in the adaptive CRT arm of the trial reached the primary composite endpoint, but the difference between this arm and the conventional CRT arm was a reduction in the primary endpoint of only 11% for the adaptive arm (hazard ratio [HR], 0.89; 95% confidence interval, 0.78 - 1.01; P = .077).

So, the Data and Safety Monitoring Board recommended that the steering committee stop the trial for futility, not having achieved at least a statistically significant 18% reduction in the primary endpoint. However, follow-up continued for an additional 5 months. There were no differences between the groups for a variety of secondary endpoints.

However, a twist is that some of the data were slow to be reported and came in after the trial had been stopped. Wilkoff speculated that it may have been because of the COVID pandemic or perhaps just fatigue on the part of some trial sites because of the very long, 8-year duration of the trial.

If the 43 endpoint events that were ultimately adjudicated were there at the time they did the third interim analysis, "we would not have [stopped], because it was a little bit more favorable than [at] the stopping point," he told Medscape Medical News.

In the adaptive arm, the automatic mechanism of the device turned on the adaptive CRT algorithm when it determined there was fusion pacing, or else it sent stimulation to both the RV and LV leads if there was no fusion pacing. It adjusted once per minute. In the control arm, it was up to the discretion of the investigator to adjust the atrioventricular interval directly but always with RV and LV stimulation.

The post hoc analysis showed a 24% reduction in mortality and HF-related events (HR = 0.76; P = .0037) for adaptive CRT if LV pacing occurred 85% or more of the time after adjusting for covariate events, compared with conventional CRT. Patients in the adaptive CRT group whose adaptive pacing occurred less than 85% of the time were indistinguishable from the conventional CRT group on the primary outcome.

Strictly speaking, missing the primary endpoint makes this a negative trial, "and that's the way these things are judged," Wilkoff noted. "But still, what we didn't fail is that we got the very best outcomes of any CRT trial over the longest period of time" in a very large trial of patients with HF, LBBB, and intact right atrioventricular conduction, suggesting "a greater overall benefit of CRT in this population than previously reported."

In both the adaptive and the conventional CRT groups, the response rates were high, and overall mortality was low. Among all randomized patients, mortality was 16.5% at 60 months postrandomization and differed by NYHA class — 12.0% for class II and 20.9% for class III/IV.

The study also demonstrated longer battery life and 41% fewer device replacements for battery depletion over 8 years of follow-up because it did not have to power right heart stimulation.

Wilkoff cautioned that the trial enrolled a highly responsive group of patients, those with left bundle branch block only and intact atrioventricular conduction, "and therefore, results may not be applicable to broader CRT populations."

Non-Timely Reporting

Designated discussant Jan Steffel, MD, University of Zurich, Switzerland, started his comments by saying that AdaptResponse was "a very important trial," but "when you come up with these curves and such an unfortunate P-value of 0.077, especially in the context of... the non-timely reporting of these 43 additional events, that is really a shame."

But he said it is important to not make a type 2 error by ignoring the positive lessons of the trial.

"There's definitely no indication of harm, and there's a good indication that this actually does work," Steffel said. He pointed out that the patients were a CRT population and not ones with implantable cardioverter defibrillators.

"So, these patients actually have disease modifying electrical therapy on board," but without what would be considered optimal medical therapy today, as they were not on SGLT2 inhibitors but did very well, nonetheless, with "major implications, both for clinical practice, but also for ongoing trials."

He also commented on the lower battery drain from the adaptive algorithm for LV-only pacing. Better battery longevity translates into fewer box changes, with implications for cost, infection risk, morbidity, and possibly mortality.

Steffel asked whether there is any reason not to use adaptive CRT in the right patient population. "With the data that has been presented so far, I do not see one,” he noted. “I think this is a very important message. We need to refer these patients, those that are eligible to CRT...we need to implant these patients, because they will have a benefit from a morbidity and from mortality point of view."

At this point, though, he cautioned against extrapolating these results to other, similar algorithms and manufacturer's devices until studies on them are in hand.

European Heart Rhythm Association (EHRA) 2023. Presented April 17, 2023.

The study was sponsored by Medtronic. Wilkoff was principal investigator and chair of the steering committee for the AdaptResponse trial. He has participated in Physician Advisory Committees of Medtronic, Abbott, Boston Scientific, Biotronik, and Philips, and has received honoraria from these companies as well as from Cook. Steffel reported consulting and speaking for Abbott, Alexion, AstraZeneca, Bayer, Berlin-Chemie, Biosense Webster, Boehringer Ingelheim, Boston Scientific, BMS, Daiichi Sankyo, Medscape, Medtronic, Menarini, Merck/MSD, Organon, Pfizer, Saja, Servier, and WebMD. He reported ownership interests in Swiss EP and CorXL.

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