STEP-HFpEF: Semaglutide in patients with HF & ejection fraction >=45% & obesity, with or without diabetes

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Pooled analysis of STEP-HFpEF & STEP-HFpEF DM. Lancet 2024

STEP-HFpEF main paper. NEJM 2023;389:1069-84.

STEP-HFpEF DM main paper. NEJM 2024;390:1394-407.

Bottom line: In patients with symptomatic HF, ejection fraction >=45% & BMI >=30, semaglutide improved quality of life & reduced weight (average ~11% weight loss at 1 year), but increased the risk of discontinuation due to GI intolerance. For every 100 patients treated for 1 year, 12 patients will get a noticeable improvement in their quality of life because of semaglutide, & 8 patients will discontinue it due to intolerable side-effects (mostly gastrointestinal).

Patients (n=1145 randomized)

  • 13 countries, 2021-2022

  • Included:

    • Age >=18 years

    • Symptomatic (NYHA 2-4) HF with left ventricular ejection fraction >=45%

    • At least one of the following:

      • Elevated LV filling pressures;

      • Elevated BNP/NTproBNP plus echocardiographic abnormalities;

      • HF hospitalization in the last 12 months, plus ongoing treatment with diuretics OR echo abnormalities

    • BMI >=30

    • Kansas City Cardiomyopathy Questionnaire (KCCQ)-Clinical Summary Score (CSS) <90/100

    • 6-minute walk distance (6MWD) >=100 meters

    • STEP-HFpEF excluded patients with diabetes (prior dx, A1c >=6.5% at screening), whereas STEP-HFpEF DM required types 2 diabetes & A1c <=10%

  • Key exclusions:

    • ESRD or dialysis dependence

  • Baseline:

    • Age 70 y, male ~50%

    • White 90%, Black 4%

    • LVEF median 57% (45-49% in 16%)

    • NYHA 2 (69%), 3 (31%)

    • KCCQ-CSS median 59/100, 6MWD median 295 meters

    • HF hospitalization in last year 17%

    • Weight median 104 kg, BMI median 37 (66% BMI >=35)

    • Comorbidities: AF 45%, CAD 21%, HTN 84%

    • Meds: Loop diuretic 62%, ACE/ARB/ARNI 79%, beta-blocker 81%, MRA 34%, SGLT2i 20% (4% in those without T2DM)

Intervention: Semaglutide subcutaneous once weekly at “weight loss doses”

  • Starting dose: 0.25 mg q1w

  • Titration: Uptitrated every 4 weeks (to 0.5 -> 1.0 -> 1.7 -> 2.4 mg q1w) as tolerated

  • Target dose: 2.4 mg q1w (reached after 16 weeks)

    • 84% of those still taking the drug at 1 year received the target dose

Comparator: Matching placebo

Outcomes @ median 1.1 year

Co-primary outcomes: Mean change from baseline to week 52:

  • KCCQ-CSS mean difference +7.5

    • Clinically-important improvement (>=5-point improvement) in KCCQ-CSS: 74% vs 57% (+17%)

      • >=10-point improvement: 61% vs 43% (+18%)

    • Consistent mean improvement over placebo across KCCQ-Overall Summary Score (+7.4) & across all sub-scores

  • Weight mean difference -8.4% or -8.9 kg (greater weight loss in non-diabetic patients)

    • >=20% reduction: 12.2% vs 1.2% (NNT ~9)

Key secondary outcomes

  • 6MWD: mean +17 meters with semaglutide vs placebo

  • Exploratory composite (time to first HF hospitalization, urgent visit, or CV death): 2% vs 6% (hazard ration 0.31, 95% confidence interval 0.15-0.62)

Safety

  • Serious adverse events: Semaglutide 28.7 vs 52.7 %/y

  • Discontinued due to GI adverse events: 10.7 vs 3.3 %/y

Internal validity = low risk of bias

  • Computer-generated random sequence generation

  • Allocation concealment by centralized interactive web-based response system

  • Blinding by matching placebo & titration schedule

  • Intention-to-treat analysis

  • Loss to follow-up (LTFU): KCCQ data missing for 8% on semaglutide & 11% on placebo at 1 year

Generalizability & other considerations

  • Similar improvement (no significant treatment-subgroup interaction) in QoL with semaglutide across studied LVEF in mildly-reduced/preserved range (45% to >=60%)

  • In STEP-HFpEF, similar improvement in QoL with semaglutide regardless of BMI (but all >=30), but KCCQ-CSS improvement in the semaglutide group was associated with weight loss >=5%

    • Impossible to say whether lesser KCCQ improvement in patients who lost <5% of their body weight due to an actual cause-effect relationship between weight loss & QoL improvement, or whether this is confounded by some other factor (e.g. lower adherence to semaglutide could explain lack of both weight loss & QoL improvement)

  • Individual-patient-level meta-analysis of patients with HFmrEF/HFpEF in STEP-HFpEF, STEP-HFpEF-DM, SELECT, and FLOW trials

    • Reduction in HF composite (time to first worsening HF or CV death): HR 0.69 (0.53-0.89); absolute risk reduction ~0.9%/y

    • But no significant reduction in CV death (HR 0.82, 0.57-1.16)

TOPCAT & FINEARTS-HF: Spironolactone & finerenone in heart failure with ejection fraction >40%

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TOPCAT (spironolactone) & FINEARTS-HF (finerenone)

Bottom line:

  • In patients with HF with EF >40% (i.e., HF with mildly-reduced or preserved EF), MRAs reduced the risk of HF hospitalization vs placebo, did not reduce the risk of dying, and increased the risk of hypotension, hyperkalemia, and eGFR reduction.

  • For every 1000 patients treated with an MRA per year, 15 HF hospitalizations would be avoided, but there would be 20-30 more people with hypotension (with or without symptoms), 70-130 more patients with eGFR reduced by >30%, and 70-80 more patients with K >5.5 mmol/L.

  • There is no direct head-to-head comparison of finerenone vs spironolactone. Efficacy & safety seem to be similar with these 2 drugs; this likely represents a class effect of MRAs in HFmrEF/HFpEF.

TOPCAT 

TOPCAT: Spironolactone for heart failure with preserved ejection fraction. NEJM 2014;370:1383-92

TOPCAT-Americas: Circulation 2015;131:34-42

Patients (n=3445)

  • Inclusion

    • Age 50+

    • Clinical HF

    • LVEF >45% (measured within 6 months prior to randomization & after any prior ACS)

    • Controlled SBP (<140, or <160 if receiving 3+ antihypertensives)

    • Either,

      • 1+ HF-related hospitalization in prior 12 months, or

      • BNP >100 pg/mL (or N-terminal pro-BNP >360 pg/mL) within 30 days, not explained by another disease entity

  • Exclusion

    • Pericardial constriction

    • Hemodynamically significant uncorrected primary valvular heart disease

    • Infiltrative or hypertrophic obstructive cardiomyopathy (HoCM)

    • Stroke, MI or CABG in past 90 days

    • AF with resting HR >90 bpm

    • Heart transplant recipient or currently implanted LVAD

    • Chronic pulmonary disease: Requiring home O2 or PO steroids, hospitalization for exacerbation within 12 months, or significant in the opinion of the investigator

  • "Average" patient

    • Age 69 y (age 75+ 27%), female 52%, white 89%

    • HF characteristics

      • Hospitalization in last 12 months 71%

      • NYHA functional class 1 (3%), 2 (64%), 3 (33%), 4 (<1%)

      • BNP 236

      • LVEF 56%

    • BP 130/80 mm Hg

    • Meds: Diuretic 80%, ACEI/ARB 85%, beta-blocker 75%

Intervention: Spironolactone

  • Initial dose: 15 mg PO daily x4 weeks

    • If initial dose tolerated, increased to 30 mg daily

    • If HF still symptomatic at month 4, increased to 45 mg daily

  • Monitoring: Measurement of SCr & serum K required <1 week after start or change of study drug dose

Comparator: Matching placebo

Outcomes @ mean 3.3 y

Efficacy

  • Death: Spironolactone 14.6% versus placebo 15.9%, hazard ratio (HR) 0.91 (95% confidence interval 0.77-1.08)

  • Hospitalization for any cause: 44.5% vs 46%, HR 0.94 (0.85-1.04)

  • Primary outcome (CV death, aborted cardiac arrest, HF hospitalization): 18.6% vs 20.4%, HR 0.89 (0.77-1.04)

  • Quality of life

    • Kansas City Cardiomyopathy Questionnaire (KCCQ; 100-point scale, minimal clinically important difference -5): Versus placebo, +1.5 at 4 months & +1.9 at 36 months (p=0.02)

Safety

  • Discontinuation of study drug: 34.3% vs 31.4%

  • Doubling of SCr: 10.2% vs 7% (NNH 32)

  • Hyperkalemia (serum K >5.5 mmol/L): 18.7% vs 9.1% (NNH 11)

Internal validity

FINEARTS-HF

FINEARTS-HF: Finerenone in heart failure with mildly reduced or preserved ejection fraction. NEJM 2024

Patients (n=6001)

  • 7463 screened -> 6016 randomized -> 6001 analyzed

  • Inclusion:

    • Age >=40

    • HF with NYHA 2-4

    • Outpatient or hospitalized for heart failure (hemodynamically stable off inotropes)

    • Receiving diuretic >=30 days

    • LVEF >=40% measured in last year (could be <40% before)

    • Structural heart abnormality (LA enlargement, LVH)

    • NTproBNP >=300 pg/mL in SR or >=900 pg/mL in AF

  • Key exclusions:

    • SBP <90 mm Hg

    • eGFR <25

    • K >5.0 mmol/L; prior hyperkalemia with MRA

    • Untreated HTN; alternative causes for HF symptoms

  • “Average” trial patient:

    • 72 y/o, 46% female, white 79%/Asian 17%

    • PMHx: HTN 88%, T2DM 42%, AF 38%, prior LVEF <40% 5%

    • HF characteristics

      • Prior HF hospitalization 60%

      • Time since HF event: <=1 week 20%, 7-90 days 34%, >3 months/none 46%

      • NYHA 2 (69%), 3 (30%), 4 (<1%)

      • LVEF 52% (36% <50%)

      • NTproBNP ~1000

    • SBP 129 mm Hg, K 4.4 mmol/L, eGFR 62

    • Meds: Loop diuretic 87%, beta-blocker 85%, ACEI/ARB ~70%, ARNI 8-9%, SGLT2i 13-14%, GLP1-RA 2-3%

Intervention: Finerenone

  • If eGFR >60:

    • Starting dose: Finerenone 20 mg PO once daily

    • Increase to 40 mg PO once daily after 4 weeks (target dose)

    • Dose range 10-40 mg daily

  • If eGFR 25-60:

    • Starting dose: Finerenone 10 mg PO once daily

    • Increase to 20 mg PO once daily after 4 weeks (target dose)

    • Dose range: 10-20 mg daily

Comparator: Matching placebo

Outcomes @ median 2.7 y

Efficacy

  • Death: 16.4% vs 17.4% (HR 0.93, 95% CI 0.83-1.06)

  • Primary outcome (composite of cardiovascular death or worsening HF event [first or recurrent hospitalization or urgent visit for HF]):

    • Finerenone 14.9 vs placebo 17.7 per 100 patient-years

    • Rate ratio 0.84, 95% confidence interval (CI) 0.74-0.95

    • Similar result using traditional “time to first event”: 20.8% vs 24.0% (hazard ratio [HR] 0.84, 95% CI 0.76-0.94)

    • Results consistent across subgroups

  • Kidney composite outcome (sustained eGFR decrease ≥50%, sustained eGFR to <15, or initiation of long-term dialysis or kidney transplantation): 2.5% vs 1.8% (HR 1.33, 95% CI 0.94-1.89)

  • NYHA improvement at 12 months: ~19% in both groups (odds ratio 1.01, 95% CI 0.88-1.15)

  • Change from baseline in Kansas City Cardiomyopathy Questionnaire (KCCQ) total symptom score: +1.6 (95% CI +0.8 to +2.3) out of 100

Safety

  • Discontinued study drug: 20% in both groups

  • SBP <100 mm Hg (symptoms not specified): 18.5% vs 12.4%

  • Hyperkalemia (K >5.5 mmol/L): 14.3% vs 6.9%

    • >6: 3% vs 1.4%

    • “Investigator-reported hyperkalemia”: 9.7% vs 4.2%

    • Death from hyperkalemia: 0% in both groups

  • Serum creatinine increase to >221 umol/L: 2% vs 1.2%

Internal validity

  • Low risk of bias

    • Allocation bias: Randomized, allocation concealed

    • Performance & detection bias: Patients, clinicians, outcome assessors unaware of treatment assignment

    • Attrition bias: Intention to treat analysis; low loss to follow-up (~0.1%)

Meta-analysis

Mineralocorticoid receptor antagonists in heart failure: an individual patient level meta-analysis. Lancet 2024

Pooled results of TOPCAT + FINEARTS-HF:

  • Composite of cardiovascular death or HF hospitalization pool: HR 0.87 (95% CI 0.79-0.95), 1.5% absolute risk reduction

  • Death: HR 0.94 (0.85-1.03)

Safety: Similar absolute increase (vs placebo) with both spironolactone & finerenone

  • SBP <90 mm Hg:

    • TOPCAT: Spironolactone 4% vs placebo 2%

    • FINEARTS-HF: Finerenone 5% vs placebo 3%

  • eGFR reduction >30%:

    • TOPCAT: 31% vs 24%

    • FINEARTS-HF: 35% vs 22%

  • K >5.5 mmol/:

    • TOPCAT: 12% vs 5%

    • FINEARTS-HF: 15% vs 7%

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