Training Regimens Fall Short in Trial Leave a comment


Exercise promotes conditioning and boosts quality of life in patients with heart failure with preserved ejection fraction (HFpEF), so different training regimens have been proposed for getting the most out of it. But a randomized trial suggests that one such proposal, high-intensity interval exercise, may not achieve better results than a more conventional training regimen.

Another potential lesson for its researchers, however, is that there might not be a single form of exercise training that is ideal for all patients with HFpEF, a clinical condition with a range of causes that may each respond to therapies differently.

The multicenter study of 180 patients with HFpEF showed similar gains in exercise capacity from two different exercise training regimens, both of which were supervised for the first few months and thereafter conducted at home.

The improvements failed to reach a prespecified goal, officially rendering the study negative. But they may have been good enough to recommend either regimen to selected patients with HFpEF given their heterogeneity and the syndrome’s lack of proven treatment options, researchers say.

Peak VO2 at both 3 months and 1 year rose similarly in patients after either a high-intensity interval training regimen or one featuring more moderate continuous exercise, compared with a control group that was given standard, guideline-based recommendations for physical activity.

However, “neither group met the a-priori-defined minimal clinically important difference of 2.5 mL/kg/min compared with the guideline control at any time point,” the researchers note in their report, published February 9 in JAMA.

“These findings do not support either high-intensity interval training or moderate continuous training compared with guideline-based physical activity for patients with HFpEF,” write the authors, led by Stephan Mueller, MA, Technical University of Munich, Germany.

The 2.5 mL/kg/min standard seemed appropriate for the protocol designed about 7 years ago, which still must dictate how the study’s conclusions are framed in the report, senior author Martin Halle, MD, from the same institution, told theheart.org | Medscape Cardiology.

But with greater appreciation of HFpEF heterogeneity and more recent studies of exercise as an intervention, he said, the prespecified goal for change in peak VO2 may have been unrealistic. The marker on average went up by more than 1 mL/kg/min from baseline to month 3, which “is better than anything else we have in HFpEF, medications or other approaches.”

Moreover, it climbed by 2 to 3 mL/kg/min “or even more” in some patients initially with poor exercise capacity. “If you asked me now, I would say, from the trials we have, that 1.0 or 1.5 [mL/kg/min] is absolutely tremendous,” Halle said.

An accompanying editorial mostly agrees. The protocol’s 2.5 mL/kg/min threshold for clinical importance “was overly ambitious, because 1.0 mL/kg/min is traditionally accepted as a clinically meaningful improvement, particularly among patients with heart failure who have severely reduced baseline peak VO2,” write Ambarish Pandey, MD, MSCS, UT Southwestern Medical Center, Dallas, and Dalane W. Kitzman, MD, Wake Forest School of Medicine, Winston-Salem, North Carolina.

This “first adequately powered randomized controlled trial to test the efficacy of 2 different modalities of aerobic exercise training in HFpEF,” they state, “was rigorous, well-designed, and well-conducted.”

Other research, note the editorialists, has suggested that a high-intensity interval regimen may be superior in patients with heart failure with reduced ejection fraction (HFrEF), who — more often than those with HFpEF — usually have cardiometabolic disease. They offer potential reasons why the two training regimens performed similarly in the study.

For example, patients assigned to the more intensive training experienced more knee and hip pain, “which may have adversely affected the adherence and motivation of the high-intensity interval training participants.” Also, “patients with HFpEF are generally older, have greater functional limitations, have more frailty, and have more comorbidities and, thus, may be less amenable to high intensity interval training.”

Given its more extensive record of success in improving exercise capacity and quality of life, they write, “moderate continuous training may be the preferred exercise training approach in older patients with HFpEF.”

But the most appropriate recommendations may be more nuanced than that, Halle proposed, because HFpEF patients vary and so do the causes of their syndrome. For example, some are more frail than others and might not tolerate the high-intensity interval regimen as well. “That is not what I prescribe first for my patients,” he said. “I ways go with moderate, and then if they do well, I go with high-intensity.”

Even moderate exercise may not always be the best initial lifestyle modification for some patients with HFpEF, which is often obesity-driven, Halle said. “They might improve by weight reduction, which is also a very good approach.”

In the Optimizing Exercise Training in Prevention and Treatment of Diastolic Heart Failure (OptimEx-Clin) trial — conducted at five centers in Belgium, Germany, and Norway from 2014 to 2018 — 180 patients with chronic, stable HFpEF were assigned to one of the three exercise groups. The population, typical for a European HFpEF cohort, Halle said, included 67% women and had a mean age of 70 years and body mass index averaging 30 kg/m2.

Regimens consisted of three-times-weekly high-intensity interval training, moderate exercise training five times per week, or a one-time instruction to follow guidelines for physical activity. The interventions were supervised for the first 3 months and conducted at home from months 4 through 12, the report states.

Patient activity levels during the at-home exercise phase were monitored and documented, and feedback was provided, via a telemonitoring system that included a wearable heart-rate sensor with smartphone connectivity.

Change in peak VO2 after 3 months, the primary endpoint, averaged 1.1 mL/kg/min in the high-intensity interval training group, 1.6 mL/kg/min in the moderate continuous training group (P = .41 vs the other training intervention), and –0.6 mL/kg/min in the control group (P = .01 vs high-intensity interval training and = .001 vs moderate continuous training), as assessed at a core lab blinded to group assignment.

Halle said the ability to make more patient-specific exercise recommendations in HFpEF is still a matter for the future, “because we don’t know a lot about who does respond and who does not.” In the current cohort, “there was a proportion that had tremendous effects, there were others who didn’t change, and also a group that deteriorated” even though they were on drug therapies and had made lifestyle changes to improve their heart failure.

Mueller discloses receiving grants from the German Research Foundation. Halle reports grants from Novartis and personal fees from Bristol-Myers Squibb, Berlin Chemie-Menarini, Novartis, Daiichi-Sankyo, AstraZeneca, Roche, Abbott, Sanofi, Pfizer, Boehringer Ingelheim, and Bayer. Disclosures for the other authors are in the report. Pandey reports serving on the advisory board of Roche Diagnostics. Kitzman discloses receiving honoraria from AbbVie, Bayer, Merck, Medtronic, Relypsa, Merck, Corvia Medical, Boehringer Ingelheim, Novo Nordisk, AstraZeneca, St Luke’s Hospital, and Novartis; grant funding from Novartis, Bayer, Novo Nordisk, and AstraZeneca; and stock ownership in Gilead Sciences.

JAMA. 2021;325:542-551, 537-539. Abstract, Editorial

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