Stepping Down Antihypertensives in Frail Nursing-Home Residents Did Not Reduce Mortality: Results from the RETREAT-FRAIL Trial

Highlights

– In the multicenter randomized RETREAT-FRAIL trial, progressive step-down of antihypertensive drugs in nursing-home residents aged ≥80 with systolic BP <130 mm Hg did not reduce all-cause mortality compared with usual care.

– Deprescribing reduced the mean number of antihypertensive agents (from 2.6 to 1.5) and produced a small adjusted increase in systolic BP during follow-up (mean between-group difference 4.1 mm Hg; 95% CI 1.9–5.7).

– All-cause mortality was similar between groups (step-down 61.7% vs usual care 60.2%; adjusted HR 1.02; 95% CI 0.86–1.21), and adverse-event rates were not apparently different.

Background and clinical context

Hypertension is highly prevalent in older adults and contributes substantially to cardiovascular morbidity. However, management in very old, frail patients—particularly nursing-home residents—presents competing priorities: reduction of long-term cardiovascular risk versus short-term harms from hypotension, falls, drug interactions, and polypharmacy. Trials that underpin modern BP targets (for example, SPRINT) largely excluded frail, institutionalized older adults and those with limited life expectancy. Consequently, there is substantial uncertainty about whether continuing or intensifying antihypertensive therapy provides net benefit in this population and whether deprescribing might improve outcomes or quality of life.

Study design

The RETREAT-FRAIL study (NCT03453268) was a multicenter, randomized, controlled trial conducted in France that enrolled nursing-home residents 80 years of age or older who were taking more than one antihypertensive medication and had a systolic blood pressure (SBP) below 130 mm Hg. Participants were randomized 1:1 to a protocol-driven progressive reduction of antihypertensive treatment (step-down group) or to usual care. Patients were followed for up to 4 years with a median potential follow-up of 38.4 months.

The trial’s prespecified primary endpoint was all-cause mortality. Secondary endpoints included change in the number of antihypertensive drugs from baseline to the last visit and change in systolic blood pressure over the follow-up period. Safety and adverse events were also recorded. The study was funded by the French Ministry of Health and others and reported in the New England Journal of Medicine (Benetos et al., 2025).

Key results

Enrollment and baseline characteristics

A total of 1,048 patients were randomized: 528 to the step-down group and 520 to the usual-care group. All enrolled participants were aged ≥80 years, living in nursing homes, receiving more than one antihypertensive drug, and had baseline SBP <130 mm Hg.

Medication burden and blood pressure

Between baseline and the last trial visit, the mean (±SD) number of antihypertensive drugs used decreased from 2.6±0.7 to 1.5±1.1 in the step-down group and from 2.5±0.7 to 2.0±1.1 in the usual-care group. Thus, the intervention achieved a clinically meaningful reduction in polypharmacy.

The adjusted mean between-group difference (step-down minus usual care) in the change in systolic blood pressure during follow-up was 4.1 mm Hg (95% confidence interval [CI], 1.9 to 5.7), indicating a modest increase in SBP in the step-down group compared with usual care.

Mortality and adverse events

Death from any cause occurred in 326 patients (61.7%) in the step-down group and in 313 patients (60.2%) in the usual-care group. The adjusted hazard ratio (HR) for all-cause mortality was 1.02 (95% CI, 0.86 to 1.21; P = 0.78), showing no evidence that deprescribing reduced mortality.

Reported adverse-event rates were similar between groups, and investigators did not identify an excess of serious adverse events attributable to the step-down strategy in the summary report.

Interpretation of effect sizes

The step-down intervention produced a meaningful reduction in the number of antihypertensive medications and a small, statistically clear rise in mean systolic BP (~4 mm Hg). However, this physiologic change did not translate into detectable changes in all-cause mortality over approximately three years, and adverse-event rates were similar. The trial therefore provides high-quality randomized evidence that, in this specific population, routine de-intensification of antihypertensive therapy does not lower overall mortality.

Expert commentary and clinical implications

RETREAT-FRAIL addresses a critical evidence gap: the effects of deprescribing antihypertensive medications among very old, frail, institutionalized patients with already low SBP. Its randomized design, multicenter conduct, and substantial sample size strengthen confidence in the primary negative finding.

What this means for practice

– Routine stepwise discontinuation of antihypertensive medications in nursing-home residents aged ≥80 with SBP <130 mm Hg should not be expected to reduce all-cause mortality.
– Deprescribing did reduce medication burden. That may nevertheless be a worthwhile goal for selected patients to reduce pill burden, potential drug–drug interactions, or symptomatic hypotension, but clinicians should not anticipate a survival benefit based on the present data.
– The modest rise in SBP (~4 mm Hg) suggests that blood pressure increases after deprescribing are usually small and may be acceptable for many patients, but monitoring is necessary.

Where individualized care still matters

Decisions about antihypertensive deprescribing should remain individualized. Potential indications for medication reduction—symptomatic orthostatic hypotension, recurrent falls, adverse drug effects, patient preference, frailty with limited life expectancy, or high medication burden—remain reasonable justifications. Conversely, for residents with compelling indications for continued BP control (recent heart failure exacerbation, recurrent stroke, or other high-risk features), clinicians may choose to continue therapy.

Guideline context

Major hypertension guidelines emphasize individualized targets in older or frail patients. Trials supporting intensive BP lowering (for example, SPRINT) excluded many frail, institutionalized older adults, limiting direct applicability to RETREAT-FRAIL’s population. RETREAT-FRAIL therefore provides needed evidence to inform guideline recommendations about deprescribing in the frailest populations.

Strengths and limitations

Strengths

– Randomized, multicenter design and robust sample size for the primary outcome.
– Clinically relevant population (nursing-home residents aged ≥80 with polypharmacy and low SBP) that is frequently underrepresented in trials.
– Clear, pragmatic intervention that achieved substantial medication reduction.

Limitations

– The summary report does not detail masking; the trial’s pragmatic, protocol-driven approach likely limited blinding and may permit performance bias (although mortality is an objective outcome).
– Cause-specific mortality and detailed cardiovascular event rates are not provided in the summary; the trial may not have been powered to detect modest differences in cardiovascular events.
– Generalizability is limited to similar nursing-home, frail populations with baseline SBP <130 mm Hg; findings do not apply to community-dwelling older adults, those with higher baseline BP, or younger patients.
– Important patient-centered outcomes (quality of life, cognition, orthostatic symptoms, falls frequency) either were not primary endpoints or are not reported in the summary; these outcomes could still favor deprescribing in some patients.
– Information about treatment adherence, crossover, and reasons for stopping medications is not detailed in the summary and could affect interpretation.

Research and practice gaps

Future analyses and trials should examine cause-specific mortality and cardiovascular outcomes, as well as symptomatic outcomes important to patients (falls, orthostatic hypotension, cognition, functional status, and quality of life). Trials comparing alternative deprescribing algorithms and those incorporating shared decision-making with explicit patient-centered outcomes would be valuable. Economic analyses examining cost and resource implications of reduced medication burden in care homes could also inform policy.

Conclusion

In frail nursing-home residents aged 80 years or older receiving multiple antihypertensive medications and with SBP <130 mm Hg, a protocolized step-down of antihypertensive therapy reduced drug burden and produced a modest rise in SBP but did not reduce all-cause mortality over ~3 years. Clinicians should not expect a survival advantage from routine deprescribing in this population but may still consider deprescribing on an individualized basis to address polypharmacy, symptoms, or patient preferences. Further work is needed to define effects on quality of life, functional status, and cardiovascular events.

Funding and trial registration

Funded by the French Ministry of Health and others. RETREAT-FRAIL ClinicalTrials.gov number: NCT03453268.

References

1. Benetos A, Gautier S, Freminet A, et al.; RETREAT-FRAIL Study Group. Reduction of Antihypertensive Treatment in Nursing Home Residents. N Engl J Med. 2025 Nov 20;393(20):1990-2000. doi: 10.1056/NEJMoa2508157 . Epub 2025 Aug 29. PMID: 40879421 .

2. SPRINT Research Group; Wright JT Jr, Williamson JD, Whelton PK, et al. A Randomized Trial of Intensive versus Standard Blood-Pressure Control. N Engl J Med. 2015;373:2103–2116.

3. Williams B, Mancia G, Spiering W, et al. 2018 ESC/ESH Guidelines for the management of arterial hypertension. Eur Heart J. 2018;39:3021–3104.

4. Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults. Hypertension. 2018;71:e13–e115.