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Clinical trials landscape

TL;DR — The HHD trial landscape is dominated by surrogate endpoints: BP, LV mass, fibrosis volume, strain, AF burden and device safety. REVERSE-LVH is the clearest phenotype-enriched randomized example: 78 adults with hypertension and CMR-LVH had greater interstitial-volume regression with sacubitril/valsartan than valsartan, but no clinical-outcome test (Lee 2025, PMID 40739095; NCT03553810). Intensive BP trials reduce cardiovascular events but generally do not require imaging-defined HHD (SPRINT 2021, PMID 34010531; STEP 2021, PMID 34491661). Renal-denervation trials show modest sham-adjusted BP effects; registered primary efficacy outcomes remain overwhelmingly pressure-based (Vukadinović 2024, PMID 39355923). A 2026-08-29 ClinicalTrials.gov audit found 172 HHD-tagged registrations and 65 completed randomized interventional records; two used hard cardiovascular-event primary composites, but neither tested treatment assigned to a serial imaging or biomarker remodeling target (NCT00338260; NCT00129233).

1. What counts as an HHD trial?

Tier Eligibility Typical endpoint Interpretability
A: phenotype-enriched HHD Hypertension plus prespecified LVH/fibrosis/function Remodeling and ideally clinical outcomes Highest etiologic specificity
B: hypertension with cardiac substudy Hypertension trial plus ECG/echo/CMR LVH, strain, AF, HF Strong exposure intervention, partial phenotype
C: clinical HF/AF with hypertension common Syndrome-based HF/AF outcomes Treatment relevant, not HHD-specific
D: coded/registry HHD Diagnostic code/condition tag Utilization or broad outcomes Attribution uncertain

Trial registries often tag broad conditions; the eligibility criteria and primary endpoint determine whether the study actually tests HHD.

2. Published phenotype-enriched remodeling trials

Study Design Endpoint Result/boundary
LIFE echo 916 serial echo within 9,193-person RCT LV-mass index −21.7 vs −17.7 g/m², losartan vs atenolol; P=0.021 (Devereux 2004, PMID 15326072)
Sacubitril/valsartan vs olmesartan 114 randomized, double blind CMR LV mass Greater reduction at 12 and 52 weeks (Schmieder 2017, PMID 29029087)
REVERSE-LVH 78 randomized, open label, blinded endpoint CMR interstitial volume −5.2±5.4 vs −2.5±3.1 mL; P=0.006 (Lee 2025, PMID 40739095)
Resveratrol Small randomized hypertensive remodeling study Cardiac remodeling measures Hypothesis-generating; no event endpoint (Zheng 2023, PMID 36854725)

REVERSE-LVH’s protocol prespecified 52-week CMR fibrosis volume and biomarker outcomes (Lee 2023, PMID 37674806; NCT03553810).

3. Live HHD/remodeling registry snapshot

Status below is from live ClinicalTrials.gov API retrieval on 2026-08-29.

NCT ID Study Status Design / primary focus
NCT03553810 Role of ARNi in Ventricular Remodeling in Hypertensive LVH Completed Phase 2; fibrosis volume; published REVERSE-LVH
NCT00865501 Importance of Aldosterone in HHD Completed Phase 3; spironolactone vs placebo; LV mass
NCT01893788 Eplerenone and Aliskiren in Hypertensive LVH Unknown Phase 4; CMR LVH reduction
NCT06186102 Spermidine in older adults with coronary disease/HHD Completed Phase 2; change in LV mass plus multimodal endpoints
NCT06409585 FAPI PET-MR in cardiomyopathies/HHD Recruiting Observational; fibrosis-tracer uptake
NCT05719337 Multimodality echo in pathological LVH Unknown Observational differential phenotyping
NCT04573257 Arterial stiffness and myocardial work in hypertension Unknown Observational; myocardial work
NCT05839028 LV remodeling in hypertensive Arctic rotational workers Active, not recruiting Observational; GLS
NCT05062811 BP effect on myocardial work Unknown Observational; work index/GLS
NCT07058831 Home monitoring for subclinical AF in hypertension Recruiting Observational; new AF detection
NCT01267747 PA prevalence in hypertensive AF/flutter Completed Observational; prevalence
NCT01990911 RDN prevention of subclinical AF in HHD Completed Randomized sham-controlled pilot; AF ≥6 minutes

“Unknown” is preserved rather than silently converted to completed or abandoned.

The dated 172-record screen identified two completed randomized registrations with a hard cardiovascular-event primary composite: the LIFE registration (NCT00338260) and a 1,150-person open-label comparison of valsartan with amlodipine in hypertension with glucose intolerance (NCT00129233). Neither randomized care according to achieved LV mass, strain, fibrosis or biomarker change. The evidence gap is therefore a completed treat-to-remodeling outcome strategy—not an absence of cardiovascular-outcome trials in hypertension.

4. Intensive BP trials as HHD prevention trials

Trial HHD ascertainment Cardiovascular result Remodeling result
SPRINT No uniform imaging HHD Final primary HR 0.73 (95% CI 0.63–0.86) Multiple substudies; not treatment-to-remodeling
STEP ECG-LVH secondary analysis Primary HR 0.74 (0.60–0.92) New ECG-LVH HR 0.76; regression unchanged
ACCORD BP No uniform imaging HHD Primary HR 0.88 (0.73–1.06) Not an HHD endpoint trial
HYVET No uniform imaging HHD HF reduction 64% (42–78) No phenotype-enriched mechanism

Sources: SPRINT 2021 (PMID 34010531), STEP 2021 (PMID 34491661), Deng 2023 (PMID 37259845), ACCORD 2010 (PMID 20228401), HYVET 2008 (PMID 18378519).

These trials prove prevention benefit in their populations, not an HHD-specific imaging threshold or mediation pathway.

5. Renal denervation published evidence

SYMPLICITY HTN-3 found six-month sham-adjusted office systolic difference −2.39 mm Hg (95% CI −6.89 to 2.12) and ambulatory difference −1.96 mm Hg (−4.97 to 1.06) (Bhatt 2014, PMID 24678939).

A 2024 meta-analysis of 10 sham-controlled trials and 2,478 participants found reductions of 4.4 mm Hg (95% CI 2.7–6.1) in 24-hour and 6.6 mm Hg (3.6–9.7) in office systolic BP (Vukadinović 2024, PMID 39355923).

Other recent meta-analyses broadly confirm modest pressure efficacy but differ by device, medication state and trial generation (Dantas 2024, PMID 39395908; Ogoyama 2024, PMID 38831091; Singh 2023, PMID 37545184).

6. Live renal-denervation registry snapshot

NCT ID Program Status Primary efficacy focus
NCT01418261 SYMPLICITY HTN-3 Completed Office systolic BP
NCT02439749 SPYRAL HTN-OFF MED pivotal Completed 24-hour ambulatory systolic BP plus safety
NCT02649426 RADIANCE SOLO/TRIO Active, not recruiting Daytime ambulatory systolic BP
NCT03614260 RADIANCE II Active, not recruiting Daytime ambulatory systolic BP plus safety
NCT05326230 RADIANCE-HTN DUO Active, not recruiting 24-hour ambulatory systolic BP
NCT02910414 TARGET BP I Active, not recruiting Mean systolic ABPM
NCT05198674 SPYRAL AFFIRM Global Active, not recruiting Six-month office systolic BP
NCT07013929 Spyral InSight Recruiting Primarily safety composite including clinical events

The presence of MI, stroke or death inside a safety composite is not evidence that the trial is powered to reduce those events.

7. Rhythm-focused denervation

The HHD pilot corresponding to NCT01990911 randomized 80 adults to denervation or sham. Subclinical AF occurred in 19% versus 39.5%, HR 0.40 (95% CI 0.17–0.96), with low burden and no significant between-group BP-change difference (Heradien 2022, PMID 35781044).

ERADICATE-AF randomized 302 hypertensive AF-ablation patients to pulmonary-vein isolation with or without denervation and favored the combined procedure for one-year arrhythmia freedom (Steinberg 2020, PMID 31961420).

Meta-analysis across seven small trials found AF recurrence 31.3% with ablation plus denervation versus 52.9% with ablation alone (Nawar 2022, PMID 35094013). Replication, sham control and standardized rhythm monitoring remain necessary.

8. HF trials: clinically decisive but etiologically broad

Trial EF Primary effect HHD limitation
EMPEROR-Preserved >40% HR 0.79 for CV death/HF hospitalization No uniform hypertensive attribution
DELIVER >40% HR 0.82 for worsening HF/CV death Same
PARAGON-HF ≥45% Rate ratio 0.87, P=0.06 Overall primary not significant
TOPCAT ≥45% HR 0.89, P=0.14 Geographic/phenotypic heterogeneity

Sources: Anker 2021 (PMID 34449189), Solomon 2022 (PMID 36027570), Solomon 2019 (PMID 31475794), Pitt 2014 (PMID 24716680).

9. Endpoint hierarchy

Endpoint Value Main weakness
Office/home/ABPM BP Scalable causal exposure Not cardiac injury
ECG-LVH Cheap and prognostic Low anatomical sensitivity
Echo mass/GLS Accessible remodeling Load and observer effects
CMR mass/ECV/interstitial volume Reproducible/tissue rich Cost and unvalidated surrogacy
Biomarker Scalable staging candidate Non-specific and threshold-sensitive
AF burden Mechanistic clinical endpoint Device/duration dependence
First HF hospitalization Clinically meaningful Adjudication and care-system effects
CV death/MI/stroke Highest clinical relevance Requires large, long trial

10. Trial-design priorities

  1. A prespecified HHD case definition independent of the endpoint.
  2. ABPM-confirmed pressure exposure.
  3. Core echo/CMR acquisition with central reproducibility.
  4. Competing-etiology exclusion.
  5. Patient-reported function and treatment burden.
  6. Clinical outcomes with recurrent-event handling.
  7. Mediation analysis prespecified, not post hoc.
  8. Recruitment across sex, ancestry, CKD, obesity and resource settings.

11. Negative and inconclusive evidence belongs in the map

Trial/result Correct statement
SYMPLICITY HTN-3 Neutral sham-adjusted six-month BP result
ACCORD BP Neutral primary composite, lower stroke, more treatment-attributed serious events
TOPCAT Neutral overall primary composite; fewer HF hospitalizations and more hyperkalemia
PARAGON-HF Primary rate ratio narrowly missed significance
REVERSE-LVH Positive CMR fibrosis-volume endpoint; no event inference

Selective publication of positive remodeling signals would overstate field maturity.

Open questions

  • Can a treat-to-fibrosis or treat-to-strain strategy reduce first HF or AF? (Lee 2025, PMID 40739095; Hwang 2025, PMID 40970541)
  • Which HHD phenotype is common and high-risk enough for a feasible outcome trial? (Sharp 2026, PMID 41771092)
  • Will renal denervation produce cardiovascular-event benefit proportional to modest BP reduction? (Vukadinović 2024, PMID 39355923)
  • How should trials handle the overlap of hypertension, obesity, CKD, CAD and AF without losing etiologic interpretability? (Cohen 2020, PMID 31926856)

References

  1. Lee V, et al. Effects of sacubitril/valsartan on hypertensive heart disease: the REVERSE-LVH randomized phase 2 trial. Nat Commun. 2025;16:6981. PMID 40739095
  2. SPRINT Research Group. Final Report of a Trial of Intensive versus Standard Blood-Pressure Control. N Engl J Med. 2021;384:1921-1930. PMID 34010531
  3. Zhang W, et al. Trial of Intensive Blood-Pressure Control in Older Patients with Hypertension. N Engl J Med. 2021;385:1268-1279. PMID 34491661
  4. Vukadinović D, et al. Effects of Catheter-Based Renal Denervation in Hypertension: A Systematic Review and Meta-Analysis. Circulation. 2024;150:1599-1611. PMID 39355923
  5. Devereux RB, et al. Regression of hypertensive left ventricular hypertrophy by losartan compared with atenolol: the Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) trial. Circulation. 2004;110:1456-62. PMID 15326072
  6. Schmieder RE, et al. The effect of sacubitril/valsartan compared to olmesartan on cardiovascular remodelling in subjects with essential hypertension: the results of a randomized, double-blind, active-controlled study. Eur Heart J. 2017;38:3308-3317. PMID 29029087
  7. Zheng X, et al. Effects of resveratrol supplementation on cardiac remodeling in hypertensive patients: a randomized controlled clinical trial. Hypertens Res. 2023;46:1493-1503. PMID 36854725
  8. Lee V, et al. Sacubitril/valsartan versus valsartan in regressing myocardial fibrosis in hypertension: a prospective, randomized, open-label, blinded endpoint clinical trial protocol. Front Cardiovasc Med. 2023;10:1248468. PMID 37674806
  9. Deng Y, et al. Intensive Blood Pressure Lowering Improves Left Ventricular Hypertrophy in Older Patients with Hypertension: The STEP Trial. Hypertension. 2023;80:1834-1842. PMID 37259845
  10. ACCORD Study Group. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med. 2010;362:1575-85. PMID 20228401
  11. Beckett NS, et al. Treatment of hypertension in patients 80 years of age or older. N Engl J Med. 2008;358:1887-98. PMID 18378519
  12. Bhatt DL, et al. A controlled trial of renal denervation for resistant hypertension. N Engl J Med. 2014;370:1393-401. PMID 24678939
  13. Dantas CR, et al. Systematic Review and Meta-Analysis of Second-Generation Sham-Controlled Randomized Trials of Renal Denervation Therapy for Patients with Hypertension. High Blood Press Cardiovasc Prev. 2024;31:669-676. PMID 39395908
  14. Ogoyama Y, et al. Effects of renal denervation on blood pressure in patients with hypertension: a latest systematic review and meta-analysis of randomized sham-controlled trials. Hypertens Res. 2024;47:2745-2759. PMID 38831091
  15. Singh S, et al. Renal denervation in hypertension: An updated meta-analysis of the randomized controlled trials. Catheter Cardiovasc Interv. 2023;102:663-671. PMID 37545184
  16. Heradien M, et al. Renal denervation prevents subclinical atrial fibrillation in patients with hypertensive heart disease: Randomized, sham-controlled trial. Heart Rhythm. 2022;19:1765-1773. PMID 35781044
  17. Steinberg JS, et al. Effect of Renal Denervation and Catheter Ablation vs Catheter Ablation Alone on Atrial Fibrillation Recurrence Among Patients With Paroxysmal Atrial Fibrillation and Hypertension: The ERADICATE-AF Randomized Clinical Trial. JAMA. 2020;323:248-255. PMID 31961420
  18. Nawar K, et al. Renal denervation for atrial fibrillation: a comprehensive updated systematic review and meta-analysis. J Hum Hypertens. 2022;36:887-897. PMID 35094013
  19. Anker SD, et al. Empagliflozin in Heart Failure with a Preserved Ejection Fraction. N Engl J Med. 2021;385:1451-1461. PMID 34449189
  20. Solomon SD, et al. Dapagliflozin in Heart Failure with Mildly Reduced or Preserved Ejection Fraction. N Engl J Med. 2022;387:1089-1098. PMID 36027570
  21. Solomon SD, et al. Angiotensin-Neprilysin Inhibition in Heart Failure with Preserved Ejection Fraction. N Engl J Med. 2019;381:1609-1620. PMID 31475794
  22. Pitt B, et al. Spironolactone for heart failure with preserved ejection fraction. N Engl J Med. 2014;370:1383-92. PMID 24716680
  23. Hwang IC, et al. Left Ventricular Mass-to-Strain Ratio to Predict Change in Left Ventricular Hypertrophy and Prognosis in Hypertensive Heart Disease. J Am Heart Assoc. 2025;14:e042032. PMID 40970541
  24. Sharp A, et al. Role of natriuretic peptides and cardiac troponins in staging hypertensive heart disease: the REMODEL study. Eur J Heart Fail. 2026. PMID 41771092
  25. Cohen JB, et al. Clinical Phenogroups in Heart Failure With Preserved Ejection Fraction: Detailed Phenotypes, Prognosis, and Response to Spironolactone. JACC Heart Fail. 2020;8:172-184. PMID 31926856