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Heart-failure management

TL;DR — Once clinical HF is present, management follows HF phenotype and comorbidity evidence, not an HHD-specific regimen. SGLT2 inhibitors reduce worsening HF/hospitalization across preserved and reduced EF; HFrEF additionally has mortality/morbidity evidence for ARNI/ACEi/ARB, evidence-based beta-blocker and MRA therapy (Vaduganathan 2022, PMID 36041474; Heidenreich 2022, PMID 35363499). HFpEF treatment requires syndrome confirmation, decongestion, BP control and phenotype-specific care; EMPEROR-Preserved and DELIVER produced primary HRs 0.79 and 0.82, driven mainly by fewer HF events (Anker 2021, PMID 34449189; Solomon 2022, PMID 36027570). TOPCAT and PARAGON-HF missed their overall primary significance thresholds and should not be rewritten as uniformly positive (Pitt 2014, PMID 24716680; Solomon 2019, PMID 31475794). The unresolved HHD question is how to prevent first HF in an imaging-defined pre-HF population.

1. Confirm the syndrome before treating the label

Domain Evidence sought Common HHD pitfall
Symptoms/signs Dyspnea, fatigue, congestion, exercise intolerance Attributing all dyspnea to diastolic dysfunction
Structure/function EF, LV/LA geometry, valve/RV findings, GLS Treating preserved EF as normal heart
Filling pressure Natriuretic peptide, echo, exercise/invasive data Normal NP in obesity used to exclude HFpEF
Etiology Ischemic, valve, rhythm, infiltrative, renal and toxic causes Hypertension used as default cause
Precipitant BP surge, AF, ischemia, infection, adherence, renal change Escalation without correcting trigger

HFpEF affects heterogeneous patients and can present with congestion at rest or elevated filling pressure only during exercise (Redfield 2023, PMID 36917048; Reddy 2018, PMID 29792299).

Hypertension-to-HF reviews emphasize prevention and treatment across this continuum, while matched HHD/HFpEF phenotyping shows that atrial remodeling and higher filling pressure distinguish failure better than LVH alone (Gallo 2024, PMID 38928371; Melenovsky 2007, PMID 17222731).

2. EF categories are trial gateways, not complete biology

Category Trial convention HHD interpretation
HFrEF EF ≤40% Evaluate ischemic/other cardiomyopathy; hypertension may be contributor
HFmrEF EF 41–49% Mixed population; often treated along HFrEF continuum
HFpEF EF ≥50% Requires objective HF evidence, not EF alone
HFimpEF Prior reduced EF, now >40% Recovery does not erase relapse risk

The 2022 U.S. and 2021 ESC guidelines used these categories while emphasizing continued phenotype and etiology assessment (Heidenreich 2022, PMID 35363499; McDonagh 2021, PMID 34447992). A 2026 ESC heart-failure guideline is now indexed, but its recommendations have not yet been synthesized on this page; the European framing here therefore remains historical rather than current (Køber 2026, PMID 42661420).

3. HFrEF foundational evidence

Trial Population/comparison Primary or mortality result
PARADIGM-HF 8,442; sacubitril/valsartan vs enalapril CV death/HF hospitalization HR 0.80 (95% CI 0.73–0.87) (McMurray 2014, PMID 25176015)
DAPA-HF 4,744; dapagliflozin vs placebo Worsening HF/CV death HR 0.74 (0.65–0.85) (McMurray 2019, PMID 31535829)
EMPEROR-Reduced 3,730; empagliflozin vs placebo CV death/HF hospitalization HR 0.75 (0.65–0.86) (Packer 2020, PMID 32865377)
RALES 1,663 severe HF; spironolactone vs placebo Death RR 0.70 (0.60–0.82) (Pitt 1999, PMID 10471456)

These trials were not restricted to hypertension-attributed cardiomyopathy. Their application depends on EF, symptoms, renal function, potassium, BP and contraindications.

4. HFrEF medication framework

Therapy axis Main outcome role HHD-specific caution
ARNI/ACEi/ARB RAAS/neprilysin pathway; mortality/morbidity Hypotension, kidney function, potassium
Evidence-based beta-blocker Mortality/morbidity, rate/ischemia Start/titrate when clinically stable
MRA Mortality/morbidity Hyperkalemia and renal monitoring
SGLT2 inhibitor HF worsening and CV benefit Volume status, genital infection, ketoacidosis context
Diuretic Congestion relief Symptom treatment, not foundational mortality evidence
Hydralazine/nitrate Selected contexts BP, adherence and subgroup evidence

HHD does not justify preserving high BP to “perfuse” a stable patient, nor aggressive lowering during shock or unstable decompensation. Hemodynamic context governs.

5. HFpEF: SGLT2 trials

EMPEROR-Preserved randomized 5,988 adults with HF and EF >40%. The primary composite occurred in 13.8% with empagliflozin and 17.1% with placebo, HR 0.79 (95% CI 0.69–0.90); total HF hospitalization HR was 0.73 (0.61–0.88) (Anker 2021, PMID 34449189).

DELIVER randomized 6,263 adults with EF >40%. Worsening HF/CV death occurred in 16.4% with dapagliflozin and 19.5% with placebo, HR 0.82 (95% CI 0.73–0.92); CV-death HR alone was 0.88 (0.74–1.05) (Solomon 2022, PMID 36027570).

Across both preserved/mildly reduced EF trials (12,251 participants), SGLT2 inhibitors reduced CV death or first HF hospitalization, HR 0.80 (95% CI 0.73–0.87) (Vaduganathan 2022, PMID 36041474).

Interpretation Supported?
Reduced HF worsening/hospitalization Yes
Consistent benefit with/without diabetes Yes
Definitive stand-alone CV-mortality reduction in each HFpEF trial No
Proven prevention in asymptomatic HHD No

6. MRA in HFpEF: TOPCAT

TOPCAT randomized 3,445 adults with symptomatic HF and EF ≥45%. The primary composite occurred in 18.6% with spironolactone and 20.4% with placebo, HR 0.89 (95% CI 0.77–1.04), P=0.14 (Pitt 2014, PMID 24716680).

HF hospitalization fell (HR 0.83, 95% CI 0.69–0.99), while hyperkalemia doubled: 18.7% versus 9.1% (Pitt 2014, PMID 24716680). Geographic and enrollment heterogeneity complicate interpretation; phenogroup analyses do not replace the neutral overall primary result (Cohen 2020, PMID 31926856).

7. ARNI in HFpEF: PARAGON-HF

PARAGON-HF randomized 4,822 participants with EF ≥45%, elevated natriuretic peptides and structural disease. The rate ratio for total HF hospitalizations/CV death was 0.87 (95% CI 0.75–1.01), P=0.06 (Solomon 2019, PMID 31475794).

Pooled analyses across EF suggest benefit may extend into mildly reduced/preserved ranges and vary by EF/sex, but subgroup gradients should not be promoted above the trial’s primary result without appropriate caution (Solomon 2020, PMID 31736342; Vaduganathan 2023, PMID 37210743).

8. Congestion management

Assessment What it changes Failure mode
Weight and edema Diuretic response context Obesity and venous disease obscure
JVP/lung findings Congestion probability Limited sensitivity
Creatinine/electrolytes Safety and response Hemoconcentration mislabeled as injury without context
Natriuretic peptide Trajectory/risk Obesity, CKD, AF influence level
Urine output/natriuresis Early diuretic response Collection and timing
BP/perfusion Vasodilator/titration safety One reading overinterpreted

Loop diuretics relieve congestion but require repeated evaluation; rising creatinine may reflect hemodynamic change, persistent congestion or injury and must be interpreted with the full response.

9. Hypertension during chronic HF

Persistent hypertension increases afterload and may signal under-treated exposure, nonadherence, volume, OSA or PA. Low BP may reflect therapy, low output, autonomic disease or advanced HF.

Situation Research-informed priority
Stable HFpEF with hypertension Sustained BP control, SGLT2 evidence, congestion and comorbidity management
Stable HFrEF with hypertension Optimize outcome-modifying HF therapy, which also lowers BP
Borderline BP during titration Symptoms, perfusion, volume and competing BP-lowering drugs
Resistant hypertension plus HF Confirm ABPM/adherence; investigate secondary causes
Acute pulmonary edema with severe BP Emergency afterload/congestion strategy

The same office target cannot be imposed during acute HF, stable ambulatory HFrEF and asymptomatic HHD.

10. AF, CKD, obesity and coronary disease

AF may precipitate congestion through rapid rate and loss of atrial contribution; anticoagulation and rhythm/rate decisions follow AF evidence. CKD changes volume, potassium and drug tolerance. Obesity lowers natriuretic peptide and defines a distinct HFpEF hemodynamic phenotype (Obokata 2017, PMID 28381470).

HFpEF phenogroup studies identify clusters dominated by AF/arterial stiffness or by obesity/diabetes/CKD/inflammation, but treatment-response claims require prospective validation (Cohen 2020, PMID 31926856; Anker 2023, PMID 37461163).

This is the rationale for multiorgan phenotype-specific treatment roadmaps rather than a single “hypertensive HFpEF” regimen (Shah 2016, PMID 27358439).

11. Quality of life and outcomes

HF outcomes should include recurrent hospitalization, symptoms, functional status and mortality. The Kansas City Cardiomyopathy Questionnaire is widely used, but changes should be reported with distribution and responder thresholds, not only statistical significance.

Qualitative HF research describes fluctuating symptoms, uncertainty, restricted activity and self-management burden; these outcomes are not captured by EF or hospitalization alone (Niklasson 2022, PMID 35081667).

12. What is HHD-specific?

Evidence HHD-specific?
Broad HF drug trials No; phenotype-wide
REVERSE-LVH remodeling trial Yes, but phase 2 surrogate
BP prevention trials Hypertension-wide, not imaged HHD
HHD-to-HF longitudinal cohorts Partly, but nonrandomized

REVERSE-LVH found greater fibrosis-volume regression with sacubitril/valsartan than valsartan at similar ambulatory BP, but it did not test incident or recurrent HF (Lee 2025, PMID 40739095).

13. Where HHD is the dominant HF cause, the problem is delivery

THESUS-HF II is a contemporary prospective acute-HF cohort from Africa and found clinically assigned HHD to be the leading aetiology (576 of 1,578 presentations, 36.5%). Discharge prescription of foundational therapy was high — renin-angiotensin-aldosterone system inhibitors in 1,014 of 1,373 (73.9%), beta-blockers in 1,053 of 1,369 (76.9%), mineralocorticoid receptor antagonists in 982 of 1,366 (71.9%) and SGLT2 inhibitors in 743 of 1,359 (54.7%) — but target doses were reached in fewer than half of patients, and estimated all-cause mortality was 11.1% (95% CI 9.6–12.9) at 30 days and 20.6% (18.4–23.0) at 180 days in a cohort of median age 56.0 years; 33.7% were lost to follow-up before 180 days (Sliwa 2026, PMID 42669305).

Mortality did not differ across aetiological groups at 30 days (log-rank p=0.39) and differed at 180 days (p=0.019); the investigators conclude that short-term outcomes were not driven by demographic, aetiological or echocardiographic factors. The operational implication for HHD is that in the settings carrying the highest modeled burden, the gap is titration, follow-up and access rather than drug selection — a different failure mode from the surrogate-endpoint problem that dominates HHD trials in high-income settings. Loss to follow-up before 180 days was 33.7%, which bounds how firmly the outcome estimates can be read.

Open questions

  • Which pre-HF HHD phenotype has sufficient short-term event risk for a prevention trial? (Sharp 2026, PMID 41771092; Lee 2025, PMID 40739095)
  • Can fibrosis/strain regression guide HF therapy independently of EF and symptoms? (González 2024, PMID 38084597)
  • Which HFpEF phenogroups show reproducible treatment interaction rather than prognostic clustering? (Cohen 2020, PMID 31926856; Anker 2023, PMID 37461163)
  • How should BP targets change during decongestion and foundational-therapy titration? (Heidenreich 2022, PMID 35363499)
  • Does achieving target doses rather than any-dose prescription change HF outcomes where HHD is the dominant aetiology? (Sliwa 2026, PMID 42669305)

References

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