IV iron in HFrEF with iron deficiency

Zhou X, et al. Iron supplementation improves cardiovascular outcomes in patients with heart failure. Am J Med 2019 [epub].

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 10 at 6-12 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 pls 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) all 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).

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 (NNT 11)

  • 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

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)

  • Can IV iron therapy reduce the risk of recurrent HF hospitalizations among patients admitted for acute HF? (ongoing trial: AFFIRM-AHF)

  • 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)

TRED-HF - Withdrawal of HF meds in patients with recovered (non-ischemic) dilated cardiomyopathy

Halliday BP, et al. Withdrawal of pharmacological treatment for heart failure in patients with recovered dilated cardiomyopathy (TRED-HF): an open-label, pilot, randomised trial. Lancet 2019 Jan 5;393(10166):61-73.

Bottom Line: In patients with recovered dilated cardiomyopathy (DCM), even careful withdrawal of HF medications will result in relapse of DCM (based on clinical signs, imaging or biomarkers) in approximately 4 out of 10 patients within 6 months, compared to no deterioration in this timeframe if these medications are continued.

These medications should be considered “lifelong” medications until we have tools that can reliably predict which patients can stop them without deteriorating.

Context

  • In patients who initially have HF with reduced ejection fraction (HFrEF), recovery of ejection fraction >50% portends a more favorable prognosis

    • e.g. In one study, vs patients who had initial HFrEF followed by LVEF recovery to >50%, patients with non-recovered HFrEF had an increased risk of death, transplant or VAD placement (HR 3.4) & CV hospitalization (HR 1.8)

  • The 2017 Canadian Cardiovascular Society (CCS) heart failure (HF) guidelines recommend consideration of monitored, sequential discontinuation of HF meds in certain subsets of patients with recovered non-ischemic cardiomyopathy

    • Including: chemotherapy-related, ETOH overuse-related, peripartum, tachycardia-related, or valvular cardiomyopathy

    • If: Asymptomatic (NYHA 1), LVEF and LV volumes normalized, trigger eliminated (e.g. ETOH abstinence, HR controlled, valve repaired/replaced)

  • There is limited evidence for pharmacological treatment withdrawal in patients with HFrEF who get EF recovery

    • e.g. in an early observational study of 13 participants with DCM taking metoprolol for >2.5 years who weaned off metoprolol, 54% (7/13) experienced clinical deterioration (4 deaths & 3 patients who worsened by 1 NYHA functional class).

Design: Open-label RCT (pilot trial designed to plan larger trial)

Patients (n=51)

  • Included if:

    • 16+ y/o

    • Previous dx of dilated cardiomyopathy (DCM) with LVEF 40% or lower

    • Currently:

      • NYHA functional class 1 (no current HF symptoms)

      • LVEF 50% or higher & left ventricular end diastolic volume indexed (LVEDVi) WNL (based on cardiac MRI, or 3D echo if MRI contraindicated)

      • NT-proBNP <250 ng/L

      • Treatment with 1+ of the following HF meds: Loop diuretic, ACEI, ARB, mineralocorticoid-receptor antagonist (MRA; spironolactone or eplerenone)

  • Key exclusion criteria

    • Uncontrolled HTN (>160/100 mmHg in clinic)

    • Mod-severe valvular disease

    • Angina

    • Beta-blocker required for AF/flutter, VT, or SVT

    • GFR <30

    • Pregnant.

  • Baseline characteristics (average of both groups unless specified)

    • Median age 55 y/o (IQR 45-64), male (67%)

    • Time since dx (4.9 y), median LVEF at dx 25%

    • Cause: Idiopathic (69%), familial (14%), trigger (excess ETOH, pregnancy, anthracycline, hyperthyroidism or myocarditis; 18%), pathogenic TTN truncation (22%)

    • Time since LVEF >50% (2 y)

    • CV symptom burden (0=none, 185=severe): 10-11

    • Quality of life using Kansas City Cardiomyopathy Questionnaire (KCCQ; 0=worst, 100=best)): 94-97

    • LVEF 60%, LVEDVi 83 mL/m^2, NT-proBNP 72 ng/L

      • Global longitudinal strain median 14% (values <16% considered abnormal)

    • Meds: ACEI/ARB (100%), beta-blocker (88%), MRA (47%), loop diuretic (12%)

Intervention & Comparator

  • Intervention: Sequential discontinuation of HF meds over max 4 months, total 6 months follow-up

    • Order of drug dose reduction/discontinuation:

      • (1) Loop diuretic (reduced by 50% q2 weeks until furosemide 40 mg/d-equivalent, then D/Ced)

      • (2) MRA (reduced by 50% until equivalent to spiro 50 mg/d, then D/Ced)

      • (3) Beta-blocker (reduced by 50% until 25% target dose or lower, then D/Ced)

      • (4) ACEI/ARB (reduced by 50% until 25% target dose or lower, then D/Ced)

    • Follow-up schedule:

      • Baseline: Clinic visit, symptom & QoL questionnaire, exercise stress test, cardiac MRI, NT-proBNP

      • q4 weeks: Clinic visit & NT-proBNP

      • @ week 16: Repeat cardiac MRI

      • @ month 6: Same as baseline

  • Comparator:

    • Phase 1 (randomized phase) x6 months: Continued all HF meds per baseline

      • @ baseline & month 6: Same as intervention group

      • @ weeks 8 & 16: Clinic visit, NT-proBNP

    • Phase 2: Then, non-randomized crossover to sequential discontinuation of HF meds as per intervention protocol

Results

Primary outcome: DCM relapse in 6-month randomized phase

  • Defined as meeting 1+ of:

    • Clinical HF based on signs & symptoms

    • LVEF reduced by >10%, to <50%

    • LVEDVi increased by >10%, to above normal range

    • NT-proBNP doubled, to >400 ng/L

  • Discontinuation group 44%, control group 0% (p=0.0001) - “number needed to harm” = 3 (rounded up from 2.3)

Figure 3 from TRED-HF. Kaplan-Meier curve of time to relapsed DCM comparing discontinuation versus continuation of HF meds

Secondary outcomes:

  • Composite safety outcome (CV death, major adverse CV events, unplanned CV hospitalization): 0 in both groups

  • (Select) differences in means between groups from baseline to month 6:

    • KCCQ: -5.1 (95% CI -9.9 to -0.4; lower with discontinuation vs continuation of HF meds)

    • LVEF -9.5% (lower with discontinuation vs continuation)

    • LVEDVi +4.7 mL/m^2 (95% CI -1.5 to +11.0, p=0.14)

    • Vitals: HR +15 bpm, BP +7/+7 mmHg

    • Inconclusive: CV symptom burden, exercise time, peak VO2, log-transformed NT-proBNP

Secondary analyses including withdrawals from phase 1 + phase 2

  • DCM relapse in control group phase 2: 36%

  • Overall DCM relapse rate after HF med discontinuation: 40% (26% relapse <2 months of discontinuation)

Figure 4 from TRED-HF. Venn diagram breakdown of component of primary outcome met (includes all withdrawals from randomized phase + single-arm crossover phase)

Figure 4 from TRED-HF. Venn diagram breakdown of component of primary outcome met (includes all withdrawals from randomized phase + single-arm crossover phase)

Internal validity

  • Allocation bias: Low risk

    • Computer-generated random sequence, 1:1 allocation in permuted blocks, stratified by baseline NT-proBNP

    • Centralized allocation via online system

  • Performance bias: Low/unclear risk

    • Patients & their clinicians aware of treatment allocation; however, the study employed a standardized protocol to wean & D/C HF meds, as well as standardized monitoring

  • Detection bias

    • Low risk of bias for objective outcomes (core lab MDs reading imaging unaware of study group allocation)

    • High risk of bias for QoL outcomes (patients completed the questionnaires aware of treatment allocation)

  • Attrition bias: Low risk

    • Loss to follow-up 2% (1 participant in withdrawal group left trial after 7 days)

    • Analyzed intention-to-treat population

Other Considerations

  • We can’t yet predict which stable, recovered DCM patients will deteriorate with D/C of HF meds

    • In this trial, predictors of DCM relapse after withdrawal of therapy included: greater age, use of >2 meds, use of MRA, higher NT-proBNP, lower global radial strain on cardiac MRI, & possibly lower peak VO2

      • However, based on univariable analysis only (no adjusting for other variables) & small n of events

    • DCM etiology did not clearly predict risk of deterioration with therapy withdrawal. Some patients with a seemingly reversible cause of DCM (e.g. ETOH use, pregnancy) did have DCM relapse upon D/Cing HF meds. Therefore, presence of a trigger does not indicate that D/Cing HF meds after HF remission will be safe.

ASCEND-HF - Nesiritide for acute decompensated heart failure

O'Connor CM, et al. Effect of nesiritide in patients with acute decompensated heart failure. N Engl J Med 2011;365:32-43.

Bottom line: In patients hospitalized with acute decompensated HF, nesiritide does not provide any clinically meaningful benefit when added to standard care, & increases the risk of symptomatic hypotension (NNH 32).

Context

  • Nesiritide, a recombinant form of B-type natriuretic peptide (BNP) & the first therapeutic natriuretic peptide, was approved for use in 2001 based on surrogate benefit (reduction in pulmonary capillary wedge pressure [PCWP]) & reduction in dyspnea at 3 hours compared to placebo or nitroglycerin.
  • Meta-analyses of small nesiritide trials found a possible increased risk of AKI & death vs placebo.

Patients (n=7007 analyzed)

  • Included:
    • Hospitalized for HF (regardless of EF)
    • Within 24h of initiation of in-hospital IV treatment of HF <24h of enrolment
    • Dyspnea at rest or with minimal activity (ie leading to NYHA functional class 3-4)
    • Plus at least 1 of: RR 20+, pulmonary congestion/edema with rales 1/3 of the way up or more of the lung fields
    • Plus at least 1 objective measure of HF (congestion/edema on CXR, BNP >400 pg/mL or NTproBNP >1000 npg/mL, PCWP >20 mm hg, LVEF <40% in the previous 12 months)
  • Excluded:
    • SBP <100 mm Hg, or <110 mm Hg if using IV nitroglycerin
    • Dobutamine (at rate of 5+ ug/kg of body wt/min)
    • Milrinone, levosimendan within 30 days
    • Persistent uncontrolled HTN; ACS; severe pulmonary disease; ESRD with renal replacement therapy; clinically-significant anemia
    • "Other contraindications for vasodilators"
  • Baseline characteristics
    • Age 67 y
    • Female 34%
    • PMHx: Ischemic heart disease 60%, HTN 73%, AF 37%
    • Median ~16h from hospitalization to study drug initiation
    • SBP 124, HR 82
    • EF <40% (80%), 40% or more (20%)
    • BNP ~990 pg/mL, NTproBNP ~4500 ph/mL
    • Na 139, SCr ~106 umol/L 
    • Meds: Loop diuretic 95%, ACEI/ARB 60%, BB 58%, MRA 28%, digoxin 27%
  • Generalizability: Good; trial population is representative of patients hospitalized for ADHF, excluding those at high risk of hypotension & those on inotropes

Interventions

  • I: Nesiritide
    • Optional loading dose: 2 ug/kg IV bolus
    • Maintenance dose: 0.010 ug/kg/min continuous infusion for >24h, max 7 days
    • Median infusion duration 41h (IQR 24-48h)
  • C: Matching placebo infusion
  • Co-interventions for all: Diuretics, morphine, other vasoactive medications guided by use of a standard-of-care manual

Results

  • Co-primary outcome 1: Self-reported dyspnea on 7-point Likert scale (range markedly better to markedly worse)
    • Moderately/markedly better @ 6h: Nesiritide 44.5%, placebo 42.1% (p=0.03)
    • Moderately/markedly better @ 24h: Nesiritide 68.2%, placebo 66.1% (p=0.007)
    • Although these differences were statistically significant, they are not clinically important
  • Co-primary outcome 2: All-cause mortality or re-hospitalization for HF @ 30 days:
    • Nesiritide 9.4%, placebo 10.1% (hazard ratio [HR] 0.93, 95% confidence interval 0.9-1.08)
    • Death: 3.6% vs 4.0% (p>0.05)
  • Secondary outcomes
    • Persistent/worsening HF or death prior to discharge: Nesiritide 4.2%, placebo 4.8% (p=0.30)
  • Adverse effects
    • Symptomatic hypotension: Nesiritide 7.2%, placebo 4.0%, number needed to harm (NNH) 32 (p<0.001)
    • Asymptomatic hypotension: Nesiritide 21.4%, placebo 12.4%, NNH 12
    • eGFR decreased by >25% from baseline: Nesiritide 31.4%, placebo 26.2% (p=0.11)

Internal validity

  • Unclear risk of allocation bias (randomization & allocation concealment procedures not adequately reported)
  • Low risk of performance & detection bias (double-blind with matching placebo)
  • Low risk of attrition bias
    • Modified ITT analysis of all patients who received study drug (98% of randomized)
    • <3% loss-to-follow-up for evaluation of symptoms at 6-24h 

Other studies of nesiritide

  • 2000 NEJM study:
    • In the first part of the trial, 127 ADHF patients were randomized to double-blind treatment with nesiritide 0.015 ug/kg/min, nesiritide 0.03/ug/kg/min or placebo. At 6h, nesiritide reduced dyspnea, improved global clinical status & reduced PCWP more than placebo.
    • In the second part of this trial, 305 ADHF patients were randomized to open-label nesiritide 0.015 ug/kg/min, nesiritide 0.03/ug/kg/min or another vasoactive agent (inotrope, nitroglycerin or nitroprusside at attending physician's discretion). There was no difference in any efficacy measure between groups.
  • VMAC: This was a double-blind RCT of 489 ADHF patients comparing nesiritide to nitroglycerin IV & placebo x3h, followed by a comparison of nesiritide vs nitroglycerin x24h.
    • By 3h, nesiritide decreased PCWP (-5 mm Hg) & right atrial pressure (-3 mm Hg) more than nitroglycerin (-3 & -2) & placebo (-2 & 0). Nesiritide also reduced dyspnea @ 3h more than placebo, but not nitroglycerin.
    • There were no differences in dyspnea or global clinical status @ 24h. The rate of adverse effects was higher in the nitroglycerin group, largely due to more headaches vs nesiritide. Rates of hypotension were similar between these 2 groups.
  • ROSE: In this double-blind trial of 360 ADHF patients with renal dysfunction, there was no difference between nesiritide, dopamine or placebo in cumulative urine output or renal function after 72h of study treatment.

DOSE - Diuretic strategies (low vs high dose & IV bolus vs continuous infusion) for acutely decompensated HF

Bottom line: In patients with acutely decompensated HF patients not in cardiogenic shock,

  • Higher versus lower doses of loop diuretics did not significantly affect primary efficacy & safety outcomes
    • However, secondary outcomes consistently demonstrated a lower risk of serious adverse events (NNT 9), more rapid resolution of dyspnea & congestion, & greater weight loss (extra -1.2 kg in first 72h), at the cost of an increased risk of AKIN stage 1 AKI (NNH 12)
  • Continuous IV administration of loop diuretics does not appear to have any advantage over q12h IV boluses.

Patients (n=300)

  • Included
    • Presented for acutely decompensated HF (ADHF) within 24h
      • Diagnosed based on 1+ symptoms (SOB, orthopnea, edema) & 1+ sign (crackles, peripheral edema, ascites, pulmonary vascular congestion on CXR) of HF
    • Hx of chronic HF (any LV ejection fraction [LVEF])
    • Receiving an oral loop diuretic equivalent to furosemide 80-240 mg/d +/- chronic thiazide diuretic
  • Excluded
    • SBP <90 mm Hg
    • SCr >265 umol/L
    • Requiring IV vasodilators or inotropes
  • Average baseline characteristics
    • Age 66 y
    • Male ~74%
    • Median time from presentation to randomization ~15h
    • Ischemic CM 57%
    • Hospitalized for HF within 1 y ~75%
    • Home dose of furosemide PO ~130 mg/d
    • Clinical characteristics
      • Orthopnea ~90%
      • SBP 120 mm Hg
      • SpO2 96%
      • JVP 8+ cm 91%
      • LVEF 35% (27% with EF 50%+)
      • NT-proBNP ~680-8200 pg/mL
      • Sodium 138
      • SCr 133 umol/L
    • Meds
      • ACEI/ARB ~65%
      • BB ~85%
      • MRA ~27%

Interventions

  • Dose comparison
    • High dose: Daily IV dose = 2.5x total home PO dose
    • Low dose: Daily IV dose = total home PO dose
  • Administration method comparison
    • Continuous IV infusion
    • IV bolus dose divided as q12h administration
  • Assigned treatment continued for up to 72h, after which treatment was open-label at discretion of treating physician
    • At 48h, could either
      • Increase dose by 50%
      • Maintain same strategy
      • D/C IV & switch to open-label PO
  • At 48h:
    • Change to PO diuretics: High 31%, low 17% (p<0.001)
    • Need for dose increase
      • High 9%, low 24% (p=0.003)
      • Continuous 11%, bolus 21% (p=0.01)
  • Median dose over first 72h
    • High 773 mg, low 358 mg
    • Continuous 480 mg (160 mg/d), bolus 592 mg (~200 mg/d)

Results

At 72h

  • Primary efficacy outcome: Global assessment of symptoms (serial 0-100 visual analogue scale measurements tallied using area under the curve [AUC] from baseline to 72h, HIGHER=better)
    • High 4430, low 4171 (p=0.06)
    • Continuous 4373, bolus 4236 (p=0.47)
  • Dyspnea AUC (higher=better)
    • High 4668, low 4478 (p=0.04)
    • Continuous 4699, bolus 4456 (p=0.36)
  • Free from congestion (JVP <8 cm [<3 cm ASA], no orthopnea & trace/np peripheral edema)
    • High 18, low 11 (p=0.09)
    • Continuous 15%, bolus 14% (p=0.78)
  • Wt change (kg)
    • High -3.9, low -2.7 (p=0.01)
    • Continuous -3.6, bolus -3.0 (p=0.20)
  • Primary safety outcome: Change in SCr (umol/L) from baseline to 72h
    • High +7.1, low +3.5 (p=0.21)
    • Continuous +6.2, bolus +4.4 (p=0.45)
  • SCr increase >26 umol/L
    • High 23%, low 14% (p=0.04)
    • Continuous 19%, bolus 17% (p=0.64)

At 60 days

  • Serious adverse event
    • High 38%, low 50% (p=0.03)
    • Continuous 44%, bolus 44% (p=0.92)
  • Composite of death, hospitalization or ED visit: 42% overall, no difference between groups

No difference between groups in median length of stay (5 days for all)

Generalizability

  • Included a mix of HFrEF & HFpEF patients at high risk of HF hospitalization with moderate to high home doses of loop diuretics, a reasonable proportion of whom were receiving good HF medical therapy
  • Outcomes were clinically important and easily measurable and translatable to practice

Internal validity

  • Low risk of bias
    • 2x2 factorial randomization using permuted blocks
    • Allocation concealed
    • Double-blind, dummy-dummy design (saline placebos with identical appearance)
    • ITT analysis
    • Threshold for significance p<0.025 for coprimary outcomes (global assessment of wellbeing & change in SCr from baseline to 72h) 

 

LEADER - Liraglutide in diabetes with high CV risk

Liraglutide and cardiovascular outcomes in type 2 diabetes. NEJM 2016;375:311-22.

Bottom line: In patients with T2DM & high CV risk (~4%/year), liraglutide reduced the risk of death, MI or stroke (NNT ~50) over ~4 years versus placebo.

Notes:

  • Liraglutide's efficacy is not clearly due to its antihyperglycemic effect, but it should likely be considered as a 3rd-line agent (after metformin & empagliflozin) for patients with T2DM above their individualized A1c target;

  • Small trials raise concern for CV safety of liraglutide in HFrEF. I will personally avoid using this drug (or any GLP-1 agonist) in HFrEF until better data shows that it's safe.

 

Patients (n=9340)

  • Included
    • Type 2 diabetes (T2DM) with A1c 7% or more
    • Either
      • Age 50 y/o or greater +
        • CAD (no ACS <14 days of enrolment)
        • Cerebrovascular disease (no stroke/TIA <14 days of enrolment)
        • Peripheral vascular disease
        • HF NYHA functional class 2-3
        • CKD stage 3-5
      • Age 60 y/o or greater +
        • Micro- or macroalbuminuria
        • HTN + LVH
        • LV systolic or diastolic dysfunction
        • ABI <0.9
  • Baseline characteristics
    • Age 64 y
    • Male 64%
    • Diabetes duration ~13 y
    • PMHx
      • MI 30%
      • Stroke/TIA 16%
      • Prior revascularization 39%
      • Symptomatic CAD 9%, documented asymptomatic cardiac ischemia 26%
      • HF 14%
      • >60 y/o with micro/macroalbuminuria (11%), HTN+LVH (5%), ABI<0.9 (<3%)
    • Clinical variables
      • Wt 92 kg
      • BMI 32.5
      • BP 136/77
    • Labs
      • A1c 8.7%
      • eGFR 30-59 (21%), <30 (<3%)

 

Interventions

  • I: Liraglutide (started at 0.6 mg subcutaneously daily, uptitrated as tolerated to 1.8 mg)
    • Median dose 1.78 mg/d
  • C: Placebo
  • Patients in both groups received standard-of-care therapy to lower BP (<130/80), glucose (A1c <7%) & lipids (statin for all patients; LDL-C <2.6 mmol/L if no ASCVD, <1.8 mmol/L if ASCVD)
    • Patients in liraglutide generally had a negligibly fewer initiation medications for these risk factors during trial (e.g. statins initiated in 11% on placebo vs 9.4% on liraglutide), except for insulin initiation (started in 43% on placebo vs 29% on liraglutide)
  • Median duration of therapy 3.5 years

 

Results @ median 3.8 years

  • Composite renal outcome: 15% vs 19%, HR 0.78 (0.67-0.92)
    • Death due to renal disease: 0.4% vs 0.3%, HR 1.59, (0.52-4.87)
    • Dialysis start: 3.1% vs 3.4%, HR 0.87 (0.61-1.24)
    • Persistent doubling of SCr: 4.9% vs 5.5%, HR 0.89 (0.67-1.19)
    • New-onset persistent macroalbuminuria: 0.9% vs 12.1%, HR 0.74 (0.60-0.91) - the least important component of the composite renal outcome, & the only one driving the significant difference
  • Safety
    • Serious adverse events: Liraglutide 49.7%, placebo 50.4%
    • Any adverse event: 62.3% vs 60.8% (p=0.12)
    • Severe hypoglycemia: 2.4% vs 3.3% (p=0.02)
    • Acute gallstone disease (cholecystitis or cholelithiasis): 3.1% vs 1.9% (p<0.001)
    • Acute pancreatitis: 0.4% vs 0.5%
    • Pancreatic carcinoma: 0.3% vs 0.1% (p=0.06)
  • Surrogates
    • @ 3 months: Liraglutide ~7.2%, placebo ~8.2%; difference decreased over time (A1c 0.4% lower with liraglutide on average through trial)
    • Wt 2.3 kg lower with liraglutide vs placebo
    • HR 3 bpm higher with liraglutide vs placebo

 

Generalizability

  • This trial represents a population of patients with long-standing diabetes (~13 years) with suboptimal glycemic control (baseline A1c 8.7%) at very high CV risk (primary outcome rate ~4%/year with placebo)
    • The relative risk reduction for the primary outcome components are likely generalizable to a lower-risk population, though this will ultimately lead to a lower absolute benefit (larger NNT) & perhaps no/minimal reduction in death
  • This trial did not evaluate a "more vs less intensive" glycemic control; it randomized patients with diabetes to liraglutide, which lowers glucose, among many other things, or placebo
    • The liraglutide had better glycemic control than placebo by ~1% at 3 months, but the trial's glycemic control protocol later resulted in much smaller differences in A1c between group
    • The benefit of liraglutide in this setting may be related to improved glycemic control, weight loss, other improvements in metabolic parameters, or to a yet-undefined mechanism
  • Heart failure
    • Only 14% of patients enrolled in this trial had HF, which was not limited to patients with reduced ejection fraction/LV dysfunction. Two small trials raise concerns about the use of liraglutide in individuals with HF:
      • FIGHT: This double-blind RCT of 300 patients evaluated the effect of liraglutide vs placebo in patients with HFrEF (HF with LVEF 40% or lower) hospitalized for HF in the previous 2 weeks on clinical outcomes & LVEF, with or without T2DM. After 6 months, liraglutide did not improve the primary outcome, LVEF, distance on a 6-minute walk test, quality of life, or NT-proBNP. There was, however, a concerning increase in the secondary outcome of death, re-hospitalization/ED visit for CV reasons (liraglutide 63%, placebo 55%, HR 1.34 [1.00-1.80])
      • LIVE: Similarly, this double-blind RCT of 241 patients evaluated the effect of liraglutide vs placebo in patients with stable HFrEF (<45%) NYHA class 1-3 on LVEF. Liraglutide did not significantly improve LVEF or any other echocardiographic measurement vs placebo, but it did increase the risk of cardiac serious adverse events (10% vs 3%, p<0.05). Notably, this was a heterogeneous collection of outcomes that included VT death, VT, AF requiring DC cardioversion, ACS, worsening HF.

Internal validity

  • Risk of bias
    • Low risk of allocation & detection bias
      • Allocation concealment maintained by computerized central allocation
      • Blinding with matching placebo
      • All macrovascular & microvascular outcomes adjudicated by company blind to assigned study intervention
    • Low risk of performance bias
      • Blinding with matching placebo
      • Standardized protocols to control CV risk factors
      • More patients in the placebo group received intensification of medications to reduce CV risk factors (likely because liraglutide produced mild improvements in metabolic parameters), particularly antihyperglycemic agents such as insulin, though this should produce a "conservative bias" towards the null in favor of the placebo group
    • Low risk of attrition bias
      • Analyzed by intention-to-treat
      • Low loss-to-follow-up (3.2% did not complete trial follow-up; 0.3% for mortality)
  • Use of composite primary outcome was completely appropriate
    • All components important (even silent MI is prognostically important)
    • Biologically rational to combine these macrovascular outcomes with overlap in pathophysiology
    • Similar contribution from each component of the composite outcome; MI and stroke both had estimates of effect nearly identical to that of the composite (HR ~0.86), making it appropriate to conclude that liraglutide reduced the risk of the composite, as well as each of the individual components
  • 2-week placebo run-in period to exclude early non-adherence to subcutaneous injections
    • Not a source of bias, but does exclude those individuals least likely to be adherent long-term
  • Per FDA guidance, designed to first prove non-inferiority trial of liraglutide vs placebo (to ensure CV safety to avoid issues as seen with other diabetes drugs rosiglitazone), then - if safe - to show superiority 
    • Not a source of bias; pre-defined & appropriate