SODIUM-HF: Sodium restriction in patients with heart failure

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)

EMPEROR-Reduced: Empagliflozin in patients with heart failure with reduced ejection fraction with or without type 2 diabetes

Packer M, et al. Cardiovascular and renal outcomes with empagliflozin in heart failure. NEJM 2020;online

Bottom line:

• Among patients with symptomatic heart failure with reduced ejection fraction (HFrEF) (with or without type 2 diabetes), empagliflozin reduced the risk of a composite of CV death or HF hospitalization vs placebo (NNT 19) at 1.3 years.

• These results are consistent with those of the DAPA-HF trial, and together these trials show that SGLT2 inhibitors reduce death from any cause (NNT 59) over 1.3-1.5 years.

• Empagliflozin increased the risk of genital infections (i.e. yeast infections; NNH 91), which are generally self-limiting or resolve with over-the-counter treatment. Empagliflozin did not increase any other adverse effects in this trial.

Patients (n=3730 randomized from 7220 screened)

• Inclusion criteria

  • Heart failure (NYHA 2-4) with reduced ejection fraction (≤40% or less)

  • Receiving background guideline-directed medical therapy (GDMT) & cardiac device therapy as indicated

  • Elevated NT-proBNP with threshold dependent on heart rhythm & LVEF

    • Normal sinus rhythm (AF)

      • LVEF ≤30%: ≥600 pg/mL (≥1200 pg/mL)

      • LVEF 31-35%: ≥1000 pg/mL (≥2000 pg/mL)

      • LVEF 36-40%: ≥2500 pg/mL (≥5000 pg/mL)

• Key exclusion criteria

  • eGFR <20

  • Symptomatic hypotension or SBP <100 mm Hg

  • BMI ≥45

  • Heart transplant recipient, listed for heart transplant, LVAD in situ

  • Infiltrative or accumulation cardiomyopathy, muscular dystrophy, HoCM, or cardiomyopathy with reversible causes (e.g. Takotsubo, tachyarrhythmia-related)

• Baseline

  • Age 67, 24% female, 70% white & 18% Asian

  • NYHA 2 (75%), 3 (24%), 4 (0.5%)

  • Mean LVEF 27% (~73% ≤30%)

  • Ischemic cardiomyopathy 52%, HF hospitalization in last year 31%, AF 37%, diabetes 50%

  • HFrEF medications: ACEI/ARB 70%, ARNI 19%, BB 95%, MRA 71% (% achieving target doses not described)

  • Devices: ICD 31%, CRT 12%

  • SBP 122, HR 71

Interventions: Empagliflozin vs placebo

• Intervention: Empagliflozin 10 mg PO once daily (fixed dose)

• Control: Matching placebo

• Co-intervention in both groups: Background HFrEF GDMT

Outcomes @ median 16 months

Efficacy

• Primary outcome (CV death or HF hospitalization): Empagliflozin 19.4% vs placebo 24.7%

  • Hazard ratio (HR) 0.75 (95% confidence interval [CI] 0.65-0.86)

  • NNT 19 over 16 months (or NNT~25/year)

• Death from any cause: 13.4% vs 14.2% (HR 0.92, 95% CI 0.77-1.10)

• KCCQ-Clinical Summary Score change at 1 year: +5.8 vs +4.1 (difference 1.7, 95% CI +0.5 to +3.0)

  • KCCQ-CSS is out of 100, minimal clinically important difference ≥5)

• HF hospitalization: 13.2% vs 18.3% (HR 0.69, 95% CI 0.59-0.81)

• Composite renal outcome (chronic dialysis, renal transplant, sustained eGFR reduction ≥40%)

• Mean change in eGFR (mL/min/1.73 m^2)/year: -0.55 vs -2.28, difference 1.73 (1.10-2.37)

• Quality of life (Kansas City Cardiomyopathy Questionnaire measured at month 3, 8, 12 & end-of-study):

Safety

• Genital infections: 1.7% vs 0.6% (p=.005)

  • Complicated in 0.3% in both groups

• No difference:

  • Stopped study drug prematurely: Empagliflozin 16,3% vs placebo 18.0%

  • Symptomatic hypotension: 5.7% vs 5.5%

  • SBP change: -0.7 mm Hg (-1.8 to +0.4)

  • Volume depletion: 10.6% vs 9.9%

  • Ketoacidosis: 0 in both groups

  • UTI: 4.9% vs 4.5%

  • Hypoglyemic event: 1.4% vs 1.5%

  • Lower limb amputation: 0.7% vs 0.5%

Internal validity: Low risk of bias

• Allocation concealment by use of an interactive-response system (low risk of allocation bias)

• Blinding of participants & clinicians with use of matching placebo (low risk of performance & detection bias)

• Use of ITT analysis with 1.1% lost to follow-up (low risk of attrition bias)

Other considerations

• Practical tip: Empagliflozin is currently available in 10-mg and 25-mg tablets. The 10 mg/d dose used in EMPEROR-Reduced was based on the lack of difference between 10 mg/d and 25 mg/d in the EMPA-REG trial. The 25-mg tablets can be split in half, and the patient can be instructed to take half a 25-mg tablet (=12.5 mg) once a day. This simple intervention would cut the cost of this therapy by half (e.g. reducing the cost to ~$500/year in Canada).

• Results of a meta-analysis (without systematic review) of the 2 large HFrEF SGLT2i trials, EMPEROR-Reduced & DAPA-HF, showed no heterogeneity in efficacy outcomes between these trials. These replicate findings confirm the efficacy of SGLT2 inhibitors in HFrEF, strongly suggest a class effect, and also show no heterogeneity in the effect on death from any cause.

• Most exclusions at screening were due to patients not meeting the trial’s fairly strct NT-proBNP criteria (n=3314; 74.6% of those excluded)

  • However, this does not impact generalizability, as results are consistent with DAPA-HF, which had more lenient NT-proBNP criteria (>900 if AF/atrial flutter, >400 if HF hospitalization within 1 year, otherwise >600)

VICTORIA - Vericiguat in heart failure with reduced ejection fraction

Armstrong PW, et al. Vericiguat in patients with heart failure and reduced ejection fraction. NEJM 2020

Bottom line: In patients with heart failure (HF) with reduced ejection fraction, vericiguat compared with placebo:

• decreased the risk of HF hospitalization from 30% to approximately 27% over a median ~11 months

• did not reduce deaths

• increased the incidence of anemia (by 2%)

Participants (n=5050)

• Included:

  • Heart failure (NYHA functional class 2-4)

  • Left ventricular ejection fraction (LVEF) <45%

  • Elevated natriuretic peptides within 30 days before randomization

    • Sinus rhythm: NT-proBNP >1000 or BNP >300

    • Atrial fibrillation: NT-proBNP >1600 or BNP >500

  • HF hospitalization within 6 months (could be randomized during HF hospitalization) OR received IV diuretics without hospitalization within 3 months

• Key exclusion

  • Concurrent medications: Long-acting nitrates, phosphodiesterase-5 inhibitors (eg sildenafil), or riociguat

  • Receiving IV inotropes; received IV treatment within last 24 hours; LVAD in situ or anticipated; pre- or post-heart transplant

  • Cardiac comorbidities:

    • ACS or coronary revascularization within 2 months

    • Tachycardia-related cardiomyopathy or uncontrolled tachyarrhythmia

    • Primary valvular disease or within 3 months after valve surgery

    • Acute myocarditis, amyloidosis, sarcoidosis, Takotsubo cardiomyopathy

    • HCM

    • Symptomatic carotid stenosis, TIA or stroke within 2 months

  • Non-cardiac comorbidities: Home O2 for severe pulmonary disease; interstitial lung disease; severe liver disease

  • SBP <100 mm Hg or symptomatic hypotension

  • eGFR-MDRD <15 mL/min/1.73m^2

• 6857 screened -> 5050 randomized from September 2016 to December 2018

  • Of 1807 excluded: 1978 due to NT-proBNP or BNP below inclusion criteria, 265 unstable, 191 declined consent

• Baseline

  • Age 67, male 76%, white 64%/Asian 22%, North America 11%

  • HF duration 4.8 years

  • HF hospitalization within 3 months 67%

  • NYHA 2 (59%), 3 (40%), 4 (1%)

  • LVEF 29% (<40% in 86%)

  • NT-proBNP median ~2800

  • Comorbidities: AF 45%, CAD 58%, diabetes 47%, HTN 79%

  • SBP 121 mm Hg, HR 73 bpm

  • Hemoglobin 134 g/L, eGFR 61 (15-30: 10%)

  • HF therapies: ACEI/ARB 73%, ARNI 15%, beta-blocker 93%, MRA 70% - triple therapy 60%, ICD 28%, CRT 15%

Intervention: Vericiguat

• Starting dose: 2.5 mg once daily (taken with food)

  • Then 2 weeks later, uptitrated to 5 mg once daily

  • Then 2 weeks later, uptitrated to 10 mg once daily (target dose)

• Median achieved dose: 9.2 mg/d (90% receiving 10 mg/d)

• Dose modification criteria

  • SBP >=100 mm Hg & not on target dose: Increase dose

  • SBP 90-99: Maintain current dose

  • SBP <90

    • Asymptomatic: Decrease dose 1 level (if 2.5 mg, hold)

    • Symptomatic: Hold regardless of dose

• Adherence: 94% of patients took >80% of doses

Comparator: Matching placebo

Outcomes @ median 10.8 months

• Primary outcome (CV death or HF hospitalization): Vericiguat 35.5%, placebo 38.5%

  • Hazard ratio (HR) 0.90, 95% confidence interval (CI) 0.82-0.98

  • Consistent across all subgroups, except baseline NT-proBNP (possible harm/lack of benefit with baseline NT-proBNP >5300)

• Death from any cause: 20.3% vs 21.2% (HR 0.95, 95% CI 0.84-1.07)

• HF hospitalization: 27.4% vs 29.6% (HR 0.90, 95% CI 0.81-1.00)

• Adverse effects

  • Anemia: 7.6% vs 5.7% (p<0.01)

  • Symptomatic hypotension: 9.1% vs 7.9% (p=0.12)

  • Syncope: 4.0% vs 3.5% (p=0.3)

Internal validity: Low risk of bias overall

• Allocation bias: Low risk

  • Randomization & allocation concealment via interactive voice/web response system

• Performance bias: Low risk

  • Matching placebo for blinding of participants

• Detection bias: Low risk

  • Outcomes adjudicated by committee unaware of group assignment

• Attrition bias: Low risk

  • Analyzed intention-to-treat (ITT) population

  • 0.3% lost-to-follow-up with no difference between groups

Other considerations

• Generalizability

  • Enrolled a very high-risk HFrEF population since inclusion required both very recent HF hospitalization + elevated NT-proBNP/BNP

    • Other HFrEF RCTs have traditionally selected higher-risk patients by requiring either recent HF hospitalization OR elevated NT-proBNP/BNP (e.g. DAPA-HF or PARADIGM-HF for the latter)

    • Furthermore, cutoff for natriuretic peptides higher than prior trials (NT-proBNP in sinus rhythm >400-600 in DAPA-HF & PARADIGM-HF)

  • As a result of this higher-risk population, the absolute risk of HF hospitalization/death (& therefore absolute benefit from adding another therapy) is greater

• Comparison to other recent therapies

  • In this trial, vericiguat was added to standard HFrEF triple therapy

  • Trials of other therapies, including dapgliflozin & ivabradine have followed this similar add-on approach, whereas sacubitril-valsartan replaced the ACEI/ARB component

  • Although HFrEF therapies generally work by complementary mechanisms & likely have additive benefit, not all patients will be able to afford or tolerate the combination of all of these medications. Therefore, clinicians will need to help patients find a balance between efficacy & safety/cost/polypharmacy

    • In the absence of head-to-head comparisons from RCTs, indirect comparison using relative risk reduction (which can be combined with estimate of the patient’s prognosis) can be helpful to estimate the benefit of the different options

Indirect comparison of relative efficacy of different HFrEF pharmacotherapeutic options

DAPA-HF & DEFINE-HF: Dapagliflozin in heart failure with reduced ejection fraction

McMurray JJV, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. NEJM 2019

Bottom line:

• Among patients with symptomatic heart failure with reduced ejection fraction (HFrEF), the SGTL2 inhibitor dapagliflozin reduced the risk of a composite of CV death, HF hospitalization or urgent visit for HF requiring IV diuretics vs placebo (NNT 21), death (NNT 44) & HF hospitalizations (NNT 28) at 1.5 years in patients with OR WITHOUT diabetes.

• Dapagliflozin also improves quality of life beyond the clinically important difference as early as 12 weeks (NNT 10-14), without any differences in adverse effects (e.g. hypovolemia, kidney injury, severe hypoglycemia).

Patients (n=4744)

• From Feb 2017-Aug 2018, 8134 screened -> 4744 randomized

• Included

  • HF with ejection fraction of 40% or less (HF with reduced ejection fraction [HFrEF])

  • NYHA functional class 2-4

  • NT-proBNP

    • >900 pg/mL if AF/atrial flutter

    • >400 pg/mL if HF hospitalization within 1 year

    • >600 pg/mL if neither of the above

  • +/- type 2 diabetes

  • Stable doses (at least 4 weeks) of standard HF medications (ACEI/ARB/ARNI + beta-blocker as tolerated, + MRA)

• Key exclusion criteria: Type 1 diabetes, symptomatic hypotension or SBP <95, eGFR <30

• Baseline (average/proportions)

  • 66 y/o

  • Female 23%

  • White 70%, Asian 24%, Black 5%

  • North America 14%

  • HF characteristics

    • Etiology: Ischemic (56%), non-ischemic (36%), unknown (8%)

    • Prior HF hospitalization 47%

    • NYHA 2 (68%), 3 (32%), 4 (<1%)

    • LVEF 31%

    • NT-proBNP ~1400

  • PMHx: Diabetes 42%, AF 38%

  • Clinical variables: SBP 122, eGFR 66

  • Therapies

    • Diuretic 93%, digitalis 19%

    • ACEI 56%, ARB 27%, ARNI 11%

    • Beta-blocker 96%

    • MRA 71%

    • ICD 26%, CRT 7%

    • Antihyperglycemics (% of those with T2DM): Metformin (51%), sulfonylurea (22%), DPP4i (16%), GLP1RA (1%), insulin (27%)

Intervention & Control

• Intervention: Dapagliflozin 10 mg daily

  • Dose reduced to 5 mg/d or temporary discontinuation if acute, unexpected decline in eGFR, volume depletion, or hypotension (or to avoid these)

• Control: Matching placebo

• Standardized monitoring: Follow-up at 14 days & 60 days (focus on HF/volume assessment, adverse events, & evaluation of renal function & potassium), then q4 months

Outcomes

CV outcomes @ median 18 months

• Primary outcome (CV death, HF hospitalization, or urgent visit for HF resulting in IV therapy): Dapagliflozin 16.3% vs placebo 21.2%

  • Hazard ratio (HR) 0.74 (95% confidence interval 0.65-0.85); Absolute difference 4.9%, NNT 21

  • CV death: 9.6% vs 11.5%; HR 0.82 (0.69-0.98)

  • HF hospitalization: 9.7% vs 13.4%; HR 0.70 (0.59-0.83)

  • Consistent across subgroups (HR 0.75 for type 2 diabetes, HR 0.73 for those without diabetes)

• All-cause mortality: Dapagliflozin 11.6% vs placebo 13.9%; HR 0.83 (0.71-0.97)

Quality of life (QoL) @ month 8

• Measured using Kansas City Cardiomyopathy Questionnaire [KCCQ] total symptom score, range from 0 [worst] to 100 [best], Minimal clinically-important difference is a 5-point improvement/worsening)

• Mean change: +6.1 vs +3.3 (/100); “win ratio” 1.18 (1.11-1.26)

• Improvement 5+ points: Dapagliflozin 58.3% vs placebo 50.9%, odds ratio (OR) 1.15 (1.08-1.23)

• Deterioration 5+ points: Dapagliflozin 25.3% vs placebo 32.9%, OR 0.84 (0.78-0.90)

Safety @ median 18 months (none statistically significant vs placebo)

• Discontinuation due to adverse events: 4.7% vs 4.9%

• Volume depletion: 7.5% vs 6.8% (p=0.4); serious in 1.2% vs 1.7%

• Worsening renal function (sustained eGFR reduction >50%, ESRD [eGFR <15 >28 days], or death from renal disease): 1.2% vs 1.6%

• Amputations: 0.5% in both groups

• Fournier’s gangrene: 0 vs <0.1%

• Bone fractures: 2.1% in both groups

• Major hypoglycemia: 0.2% in both groups

• DKA: 0.1% vs 0

Lab changes (difference vs placebo)

• Weight -0.9 kg, SBP -1.3 mm Hg

• NT-proBNP -303 pg/mL

• HbA1c -0.24%

• SCr +1.8 umol/L

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

• Computer-generated randomization, stratified by presence of type 2 diabetes

• Allocation concealed by interactive voice/web-response system

• Participants, clinicians unaware of treatment assignment (blinded)

• Blinded adjudication of outcomes

• Loss-to-follow-up <0.8%

• Analysis of the intention-to-treat (ITT) population

Other trial of dapagliflozin in HFrEF: DEFINE-HF (PMID: 31524498)

• Participants (n=263)

  • Included: HF with LVEF 40% or less, NYHA 2-3, elevated natriuretic peptide (NT-proBNP 400+ pg/mL or BNP 100+ pg/mL), +/- T2DM

  • Excluded: Type 1 diabetes, HF hospitalization within last 30 days, eGFR <30

  • Baseline characteristics:

    • 61 y/o, male 73%, white 55%/black 40%

    • ischemic etiology 53%, prior HF hospitalization ~80%, HF duration 7 years

    • NYHA 2 (70%), 3 (30%), KCCQ overall summary score 67/100

    • LVEF 26%

    • T2DM 62%, AF 40%

    • SBP 123, HR 72, eGFR 65-70, HbA1c ~7%

    • Meds: ACEI/ARB 60%/ARNI 30%, BB 95-100%, MRA 60%, ICD 60%, CRT 20-30%

• Dapagliflozin 10 mg/d (intervention) vs placebo (control)

• Outcomes @ 12 weeks:

  • QoL measured using KCCQ overall summary score

    • Mean 3-point improvement with dapagliflozin vs placebo

    • Improvement of 5+ points: Dapagliflozin 43% vs placebo 33% (NNT 10)

    • Difference in KCCQ sub-domains of clinical summary score, total symptom score, physical limitation score & QoL score, but not social limitation score

  • No difference between dapagliflozin vs placebo in:

    • Change in NT-proBNP

    • Any adverse effects

• Internal validity: Low risk of bias.

IV iron in HFrEF with iron deficiency

Updated Jan 4, 2021

Bottom line: In patients with HFrEF who have iron deficiency, IV iron therapy:

• has no clear effect on all-cause or CV mortality;

• reduces the risk of HF hospitalizations (NNT 17 at 12 months);

• improves quality of life (~4-point improvement on 100-point scale), functional capacity, & walking distance.

• Current evidence does not suggest that oral iron supplementation offers any benefit.

Context

• In patients with heart failure with reduced ejection fraction (HFrEF), iron deficiency is defined as having a serum ferritin <100 ug/L OR ferritin 100-300 ug/L + transferrin saturation (tsat) <20%

• In HFrEF, iron deficiency is:

  • Present in 2/3 of patients with anemia & 1/2 of patients without anemia;

  • Associated with higher NYHA class (i.e. worse symptom burden), higher serum NT-proBNP, & higher risk of death (independent of hemoglobin concentration).

• In the IRONOUT HF trial, oral iron supplementation (using Feramax 150 mg BID x4 months) in patients with HFrEF + iron deficiency did not improve quality of life or exercise capacity;

  • Importantly, 4-months of oral supplementation only modestly improved tsat (+3%) & non-significantly increased ferritin (+11 ug/L, 95% confidence interval [CI] -0.3 to +23), suggesting that this does not efficiently replace iron stores;

  • It remains unknown if other PO iron formulations, such as sulfate or fumarate salts, may be effective in these patients;

  • Also unknown whether PO iron could adequately maintain iron stores in patients first treated with IV iron.

• 3 prior meta-analyses (Can J Cardiol 2016, Eur J Heart Fail 2016, Eur J Heart Fail 2018) demonstrated a reduction in HF hospitalizations with intravenous iron (number needed to treat [NNT] over 6-12 months of 10-12); however, these studies were limited by restrictive eligibility criteria that included only 4-5 of the ~10 randomized controlled trials (RCTs).

2019 Meta-Analysis - Zhou X, et al. Iron supplementation improves cardiovascular outcomes in patients with heart failure. Am J Med 2019;132:955-63.

Design

• Search timeframe: Database inception to March 2018

• Databases searched: PubMed, Embase, CENTRAL

• Additional measures: None

• Eligibility criteria:

  • Published in English

  • Design: Randomized controlled trial (RCT), at least single-blind

  • Population: “systolic” HF (i.e. HFrEF)

  • Intervention: Iron supplementation

• 10 trials identified (including the 2 largest trials, FAIR-HF & CONFIRM-HF)

• Risk of bias: Variable, 2 largest IV iron trials (FAIR-HF & CONFIRM-HF) rated as being at overall low risk of bias

Patients (n=1404)

• Inclusion criteria of FAIR-HF & CONFIRM-HF, the 2 largest trials:

  • HF with LVEF ≤45%

  • NYHA 2-3

  • Hb 95-135 g/L in FAIR-HF, <150 g/L in CONFIRM-HF

  • Iron deficiency (ferritin <100 ug/L or 100-300 ug/L plus tsat <20%)

• Baseline characteristics in FAIR-HF:

  • Age 67, female 55%

  • Ischemic cardiomyopathy ~80%, prior MI ~58%

  • NYHA 2 (19%) or 3 (81%); 6-minute walk test (6MWT) distance 270 m

  • LVEF ~33%

  • Hb 119 g/L, MCV 92 um^3, ferritin ~60 ug/L, tsat ~17%

  • eGFR 65 mL/min/1.73 m^2

  • Meds: ACEI/ARB >90%, beta-blocker ~85%, MRA ?, digoxin ~15%

• Baseline characteristics in CONFIRM-HF:

  • Age 69, female 45-50%

  • Ischemic cardiomyopathy 83%, prior MI 60%

  • NYHA 2 (~55%) or 3 (~45%); 6MWT distance ~290 metres

  • LVEF ~37%

  • Hb 124 g/L, ferritin 57 ug/L, tsat 18-20%

  • eGFR ~65 mL/min/1.73 m^2

  • Meds: ACEI 77%, ARB 23%, beta-blocker ~90%, MRA ?, digoxin 19-27%

Interventions

• Intervention: Iron

  • IV iron in 8 studies, with variable doses

    • e.g. mean 1850 mg given over 24 weeks in FAIR-HF, mean 1500 mg given over 1 year in CONFIRM-HF

  • PO iron in 3 studies, 200-600 mg/d

• Control: Matching placebo infusion

Results @ ~6-12 months (range 2 weeks to 1 year)

• Mortality (6 trials): Iron 3.3% vs control 4.6%; odds ratio (OR) 0.76, 95% CI 0.43-1.37

• HF hospitalizations: (5 trials, all IV iron): 5.3% vs 14.5%; OR 0.39, 95% CI 0.19-0.80

  • However, there was an important error in this analysis, with a far wider confidence interval after re-analysis

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• Quality of life (4 trials; measured with Kansas City Cardiomyopathy Questionnaire [KCCQ]): 4.1 points better with iron than control

  • KCCQ range 0-100; 5-point change considered minimally clinically important difference (MCID)

  • Note: Mean improvement over placebo of 4.4 (CONFIRM-HF), 6.6 (FAIR-HF), & 7.6 in 3 trials of IV iron vs placebo; mean improvement 0.1 in 1 trial of PO iron vs placebo (the aforementioned neutral IRONOUT HF trial)

  • Other QoL scales: EQ-5D (2 trials; 4 points better with IV iron), MLHFQ (2 trials; 19 points better with IV iron)

• NYHA functional class (5 trials): -0.7 (better) with IV iron vs control

• 6MWT (5 trials): Distance 33 m farther with IV iron vs control

• LVEF (3 trials): 3.8% higher with IV iron vs control

AFFIRM-AHF - Ponikowski P, et al. Ferric carboxymaltose for iron deficiency at discharge after acute heart failure: a multicentre, double-blind, randomised, controlled trial. Lancet 2020;396:1895-904.

Design

• RCT at low risk of bias (randomized; allocation concealed; blinding of patients; clinicians & outcome assessors; modified intention-to-treat; <0.5% loss to follow-up before 1st event)

Patients (n=1132)

• Included: Adults hospitalized for acute HF, receiving IV furosemide >=40 mg/d with LVEF <=50% & iron deficiency (per definition in context)

• Baseline:

  • Age 71, female 45%

  • Ischemic cardiomyopathy ~47%, prior MI ~40%

  • NYHA 1 (1-3%), 2 (45%), 3 (50%), 4 (~3-4%)

  • LVEF ~33%

  • Hb ~120 g/L, ferritin ~86 ug/L, TSat ~15%

  • eGFR <60 (52%)

  • Meds: ACEI/ARB/ARNI ~75%, beta-blocker 83%, MRA 65%, digoxin ~17%

Intervention: IV iron

• Ferric carboxymaltose, initial dose #1 & #2 dosed based on initial hemoglobin & patient weight, & doses #3 & #4 only if persistently iron deficient

• Initial IV bolus dose #1 - before discharge

  • Hb 140-150 g/L at any weight: 500 mg

  • Hb 80-140 g/L at any weight: 1000 mg

• Initial IV bolus dose #2 - at week 6

  • Hb >=140 g/L: No dose

  • Wt <70 kg

    • Hb 100-140 g/L: No dose

    • Hb 80-99 g/L: 500 mg

  • Wt >=70 kg

    • Hb 100-140 g/L: 500 mg

    • Hb 80-99 g/L: 1000 mg

• Mean total dose throughout trial: 1352 mg

Comparator: Matching placebo

Outcomes @ 12 months

• Primary outcome (total CV death + HF hospitalizations):

  • IV iron 57.2 vs placebo 72.5 per 100 patient-years

  • Rate ratio 0.79 (95% confidence interval [CI] 0.62-1.01)

  • Note: Rate includes recurrent HF hospitalizations

  • No difference in CV death: 14% in both groups, hazard ratio (HR) 0.96 (95% CI 0.70-1.32)

• First HF hospitalization or CV death:

  • IV iron 32% vs placebo 38% (number needed to treat 17)

  • HR 0.80 (95% CI 0.66-0.98)

  • Note: This is the more traditional & commonest way to report outcomes in HF trials

• Serious adverse events: 45% vs 51%

• Premature study drug discontinuation: 28% vs 29%

Ongoing areas of uncertainty:

• What is the long-term efficacy & safety of IV iron therapy for HFrEF? Does IV iron therapy reduce the risk of death in patients with HFrEF? (ongoing trials: FAIR-HF2, HEART-FID, IRONMAN)

• Would a different PO iron formulation be effective for iron replacement in patients with HFrEF? (ongoing trial: NCT03344523)

• What is the optimal duration, route & maintenance regimen for iron therapy following IV iron replacement?

• Is IV iron beneficial in patients with HF with LVEF >45%? (ongoing trials to assess this: FAIR-HFpEF)