The angiotensin II receptor blocker (ARB) telmisartan (Micardis) did not significantly improve walking performance in patients with lower-extremity peripheral artery disease (PAD) in a randomized controlled trial.
From baseline to 6 months, the average change in the primary outcome of 6-minute walk test distance was 1.32 m for telmisartan and 12.5 m for placebo.
The adjusted mean between-group difference was −16.8 m (95% CI, −35.9 m to 2.2 m; P = .08), suggesting, if anything, that telmisartan could be harmful for walking distance, reported Mary M. McDermott, MD, professor of medicine at the Feinberg School of Medicine at Northwestern University, Chicago, and colleagues.
“It certainly was not beneficial and, in addition to that, it did not improve any of the secondary outcomes, the patient-reported outcomes, or the treadmill walking distance. So it was definitively negative,” she told the heart.org | Medscape Cardiology.
The researchers tested telmisartan because of preliminary evidence from preclinical studies suggesting the AT1-receptor blocker has a favorable effect on blood flow and from animal models that it may repair damaged muscle and improve mitochondrial activity, McDermott explained. In addition, a small phase 2 trial from 2010 showed telmisartan significantly improved treadmill walking distance at 12 months in 36 patients with PAD.
Nevertheless, preclinical data is fairly far removed from humans and the treadmill walking distance and 6-minute walk test are two very different measures, she noted. Lower extremity atherosclerotic obstruction also may have prevented delivery of telmisartan to muscle microvasculature and 71% of participants in the trial, called TELEX, were Black — a population that has a poorer response, at least for blood pressure control to ARBs.
“Another possible explanation is that we tested telmisartan with exercise and it’s possible that combination is a bad one,” McDermott said. “I don’t have an explanation for it, but perhaps telmisartan prevents or counteracts some of the benefits of exercise.”
As reported this week in the Journal of the American Medical Association, TELEX used a 2 x 2 factorial design to randomly assign 114 patients (mean age, 67.3 years; 40.4% women) to one of four groups for 6 months: telmisartan titrated to a maximum of 80 mg or placebo, both plus supervised exercise or attention control.
Supervised exercise involved treadmill walking three times per week with an exercise physiologist, working up to 50 minutes of exercise per session. Attention control included weekly 1-hour educational sessions by faculty or staff on health topics including cancer screenings, immunizations, and hypertension.
The trial excluded patients already taking an ARB or angiotensin-converting enzyme (ACE) inhibitor, slowing enrollment. As a result, the sample size was reduced from 240 to 112 participants and the primary comparison changed to all participants randomly assigned to telmisartan (with and without exercise) vs all those assigned placebo (with and without exercise).
In all, 105 patients completed 6-month follow-up. Adherence based on pill counts was 92.6% for telmisartan and 90.4% for placebo. The mean telmisartan dose was 53.4 mg/d.
The 6-minute walk distance in the telmisartan group averaged 341.6 m at baseline and 343.0 m at 6 months, compared with averages of 352.3 m to 364.8 m in the placebo group.
Among the five secondary outcomes, there was no significant adjusted mean between-group difference at 6 months in:
Maximal treadmill walking distance (5.2 m; P = .91),
Walking Impairment Questionnaire (WIQ) score for distance (4.2; P = .40)
WIQ score for speed (-2.1; P = .66)
WIQ score for stair climbing (-1.3; P = .83)
Short Form 36 physical functioning score (1.2; P = .79)
Similarly, there was no significant effect on change at 6 months in the exploratory outcomes of Short Physical Performance Battery scores or 4-m walking velocity.
In post-hoc analyses, exercise alone significantly improved 6-minute walk distance from a mean of 326.8 m at baseline to 357.0 m at 6 months in the exercise groups compared with a mean of 376.8 m to 372.2 m in the attention control groups. The adjusted mean between-group difference was 21.3 m (95% CI, 1.4 – 41.1 m; P = .04).
“Exercise remains a first-line therapy and this study does not change that,” McDermott said.
There were 16 serious adverse events in the telmisartan group and 21 in the placebo group, with the most common being hospitalization for PAD.
The results should encourage physicians to counsel their patients with PAD who are taking telmisartan to prevent cardiovascular events that “it won’t change their walking performance and, I suppose they might say, there’s a small chance it might make it worse,” McDermott said.
Further studies of PAD therapies should look outside the renin–angiotensin pathway, she added, highlighting several alternatives currently being tested, including nitrate-rich beet juice in a crossover trial, cocoa flavanols in the COCOA-PAD II trial, and intermittent pneumatic compression with and without exercise in the INTERCEDE trial.
“What is clear now is the unmet need for further research,” Marc P. Bonaca, MD, MPH, Colorado Prevention Center in Aurora, and colleagues comment in an accompanying editorial.
They point out that the mean baseline 6-minute walk in TELEX was approximately 340 m to 350 m — a distance below normal even when considering the age of the participants — and that therapies known to be effective, such as supervised exercise, as well as statins and cilostazol (Pletal), remain underused in patients with PAD.
“Rather than waiting for patients to report they have difficulty walking even short distances, clinicians need to ask, examine, and test with particular attention those at highest risk,” Bonaca and colleagues conclude. “Beyond the clinic, greater awareness, advocacy, education, and investment are needed to solve the complex pathobiology of limb morbidity in patients with PAD. To this end, efforts such as the American Heart Association’s PAD National Action Plan and Strategically Focused Research Networks are welcome steps forward.”
The study was funded by a grant from the National Heart, Lung, and Blood Institute (NHLBI) and supported by the National Institute on Aging and the Jesse Brown VA Medical Center. McDermott reported receiving grants from the NHLBI, Helixmith, and Regeneron; consulting fees from Cambrian Biopharma; and other support from ArtAssist, HelixMith, Mars Company, ReserveAge, and Chromadex for study interventions or measures not related to the current study. McDermott is also deputy editor of JAMA. Bonaca reported relationships with multiple drug and device companies.
JAMA. Published online October 4, 2022. Abstract, Editorial
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