SODIUM-HF: Sodium restriction in patients with heart failure

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By Hans Haag with editorial support from Ricky Turgeon

SODIUM-HF. Lancet 2022;399:1391-400.

Bottom line: In patients with heart failure (HF), achieved dietary sodium restriction ~1600 mg/day did not reduce the risk of death or cardiovascular hospitalizations/ED visits compared with usual care achieving sodium about 2000 mg/day.

Patients (n=841 randomized, 806 analyzed)

  • Included:

    • Adults with clinical HF

    • NYHA class 2-3

    • Receiving optimal guideline-directed medical therapy

  • Key exclusions:

    • Dietary sodium intake <1500 mg/day

    • Serum sodium <130 mmol/L

    • eGFR <20 mL/min/1.73 m^2 or requiring hemodialysis

    • Within 1 month of cardiovascular hospitalization

  • Baseline

    • Age 67, 33% female, 58% Canadian

    • NYHA 2 (71.4%), NYHA 3 (26.9%), LVEF median 36%, NT-proBNP ~800, HF hospitalization in last 12 months ~33%

    • Comorbidities: HTN 62%, CAD 47%, AF/AFL 39%, diabetes 33%

    • SBP 118, eGFR 61

    • Meds: ACEI/ARB/ARNI 81%, beta-blocker 87%, MRA 57%

      • Diuretic use not reported

    • Baseline median sodium intake ~2200 mg/day (self-report)

Intervention: Dietary sodium intake <1500 mg/d

  • Country-specific meal plans & menus

  • Achieved ~1600 mg/d at 12 months (approximately 400 mg/d lower than comparator group)

Comparator: Usual care

  • General advice to restrict dietary sodium (as provided during routine clinical practice)

  • Achieved ~2000 mg/d at 12 months

Outcomes @ 12 months

  • No difference for any of the clinical outcomes

  • Improvements in some subjective secondary outcomes with the intervention

    • QoL: Mean difference in Kansas City Cardiomyopathy Questionnaire +3.4/100 vs placebo

    • NYHA class 1: 16% vs 11% (odds ratio 1.69 [95% CI 1.16-2.50] for improvement ≥1 NYHA class)

    • 6min walk distance (6MWD): +6.6 meters (95% CI -9 to +22)

Internal validity

  • Low risk of bias for clinical outcomes (death, hospitalizations)

    • Low risk of selection bias: Independent statistician generated randomization list; allocation concealment by automated web-based system. Block randomization according to the study site.

    • Low risk of performance & detection bias: Patients and clinicians unblinded to treatment allocation, but relatively objective outcomes & blinded endpoint adjudication

    • Attrition bias: ITT analysis, LTFU <1%

  • High risk of bias for subjective outcomes (QoL, NYHA, & to lesser extent 6MWD)

    • Low risk of selection bias as above

    • But high risk of performance & detection bias due to subjective nature of these outcomes & extra healthcare visits with in-person dietician visits at months 3 & 9 (possibility to identify & mitigate worsening HF or optimize pharmacotherapy)

  • Trial stopped early due to operational feasibility issues resulting from the COVID-19 pandemic

Other considerations

  • Generalizability: Limited to individuals already fairly restrictive in dietary sodium

    • Patients/comparator:

      • All patients were restricting sodium intake at baseline (~2.2 g/d) compared to the general population (average 4 g/day worldwide). The value of this restriction & ideal targets (e.g. 2-2.5 g/d vs 3-4 g/d) remains unknown.

      • Notably, these results do not apply to patients who are acutely hospitalized with HF, require escalating diuretic doses, or those with advanced chronic kidney disease

    • Intervention: Highly transportable/scalable due to use of meal plans & menus rather than prepared meals

  • Proportion of patients on diuretics used, doses used, & potential changes during the trial have not (yet?) been reported

    • These results could shed light on the secondary outcomes (e.g. could sodium restriction allow for lower diuretic doses -> less urinary frequency -> improve QoL?)

    • Similarly, information on changes to HF pharmacotherapy during the trial could offer further insights into these results

Context

  • Sodium restriction has historically been a cornerstone of HF management for decades due to the role of sodium in contributing to sodium retention and congestive symptoms of HF

    • However, evidence for sodium retention (& specific targets) has been limited to observational studies and small, inconclusive randomized controlled trials.

  • The latest Canadian HF guideline recommendations on dietary sodium intake (2017) acknowledged this uncertainty and recommended personalizing daily targets while still recommending 2000-3000 mg of sodium per day (consistent with the usual care group in SODIUM-HF)

PARAGON-HF: Sacubitril-valsartan in heart failure with ejection fraction >=45%

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By Hans Haag with editorial support from Ricky Turgeon

PARAGON-HF. NEJM 2019;381:1609-20

Bottom line:

  • In patients with heart failure (HF) with left ventricular ejection fraction (LVEF) ≥45%, sacubitril-valsartan did not reduce the composite total HF hospitalizations/cardiovascular (CV) death or death from any cause over ~3 years.

  • Sacubitril-valsartan increased the risk of hypotension (+5%) and angioedema (+0.4%) compared with valsartan.

  • In subgroup analyses (which often lead us astray) sacubitril-valsartan reduced HF hospitalizations in females by ~1.5%/year (but not males) with LVEF in the “lower” range (45-60%).

Patients (n=4822 randomized)

  • Screened 10,359 -> 5746 entered valsartan run-in (~9% discontinued) -> 5205 entered sacubitril-valsartan run-in (7% discontinued) -> 4822 randomized

  • Included:

    • Age 50+

    • NYHA 2-4

    • LVEF ≥45% measured in the last 6 months

    • At least one of the following:

      • HF hospitalization within 9 months prior + NT-proBNP >200 pg/mL (>600 pg/mL if AF)

      • NT-pro-BNP >300 pg/mL (>900 pg/mL if AF)

    • Echo evidence of LA enlargement (e.g. LAV ≥55 mL or LAVi ≥29 mL/m^2) or LVH (septal thickness ≥1.1 cm)

    • Symptomatic HF for at least 30 days prior to screening visit

    • Structural heart disease (LA enlargement or LVH)

  • Key exclusions:

    • Any prior LVEF <40%, history of dilated cardiomyopathy, hemodynamically significant valvular heart disease

    • Uncontrolled/life-threatening dysrhythmia, including AF-RVR

    • History of angioedema

    • Alternate diagnosis to explain HF symptoms (e.g. anemia with Hb <100 g/L, severe COPD)

    • Uncontrolled hypertension

    • SBP <100 mm Hg or symptomatic hypotension

    • eGFR <30 mL/min/1.73m^2 or a reduction of >35% after run-in period

    • K >5.2 mmol/L

  • Baseline:

    • Age 73, 52% female, 82% white, 12% Asian, 2% Black

    • NYHA 2 (77%) & 3 (20%), LVEF median 57%, NT-proBNP ~900 pg/mL, HF hospitalization in last 12 months ~23%

    • Comorbidities: HTN 96%, diabetes 43%, AF/AFlutter 33%

    • Meds: Diuretic 96%, ACEI/ARB 86%, beta-blocker 80%, MRA ~25%

    • SBP 130, eGFR 63

Interventions: Sacubitril-valsartan 97/103 mg BID vs valsartan 160 mg BID

  • Intervention: Sacubitril-valsartan 97/103 mg BID (82% on target dose)

  • Comparator: Valsartan 160 mg BID (85% on target dose)

  • Co-intervention: MRA permitted, all other non-study RAAS inhibitors stopped

Outcomes @ median 35 months (2.9 years)

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Internal validity: Low risk of bias selection, performance, detection & attrition bias

  • Selection bias: Computer-generated random sequence; allocation concealment by interactive web-response system

  • Performance & detection bias: Patients, clinicians & investigators blinded to study allocation via double-dummy placebo

  • Attrition bias: ITT analysis, LTFU <0.1%

Other considerations

  • Generalizability:

    • 16% excluded in single-blind run-in

      • Consisted of (1) Valsartan 40-80 mg BID x 1-2 weeks, then (2) sacubitril-valsartan 49/51 mg BID x2-4 weeks, then randomized

    • PARAGON-HF defined “preserved” ejection fraction as >45%, which differs from the (subsequent) 2021 universal definition and classification of HF’s classification of HF with preserved LVEF as ≥50% and HF with LVEF 41-49% as mildly-reduced

  • Pre-specified subgroup analysis of the primary outcome based on baseline LVEF suggests greater benefit with ARNI in patients with LVEF below the study median (≤ 57%) and in females (but no reduction in death in any subgroup)

  • Are the results clinically important?

    • Yes for: Patients who place higher value on reducing HF hospitalizations and improving quality of life than they do the increase in hypotension, angioedema (and higher cost)

    • Not for:

      • Males

      • Female patients with LVEF ≥60%

      • Female patients who do not care about the benefits noted above, or who are more concerned about costs, pill burden, and the adverse effects noted

    • However, given the more robust evidence and greater certainty for SGLT2 inhibitors and MRAs in this setting (noted below), ARNI should generally be offered after exhausting those other options.

Context