STEP-HFpEF & SUMMIT: Incretin analogs (semaglutide & tirzepatide) in patients with HF & ejection fraction >=45% & obesity, with or without diabetes

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Semaglutide articles

Tirzepatide articles

Bottom line:

  • In patients with symptomatic HF, ejection fraction >=45% & BMI >=30, semaglutide & tirzepatide both improved quality of life, reduced weight, & reduced worsening HF events, but increased the risk of discontinuation due to GI intolerance.

  • For every 100 patients treated with semaglutide or tirzepatide for 1 year, 12-15 patients will get a noticeable improvement in their quality of life because of treatment, 3-4 will avoid a HF event, & 5-8 patients will discontinue semaglutide/tirzepatide due to intolerable side-effects (mostly gastrointestinal).

  • The impact of semaglutide/tirzepatide on mortality in patients with HF is unknown.

Patients

Intervention: Incretin analog (semaglutide in STEP-HFpEF trials, tirzepatide in SUMMIT)

Comparator: Matching placebo

Outcomes

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

  • Low loss to follow-up (LTFU)

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% 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 are consistent with the primary outcome of SUMMIT

    • 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%

REDUCE-AMI: Beta-blockers in MI & LVEF >=50%

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REDUCE-AMI: NEJM 2024 DOI: 10.1056/NEJMoa2401479

Bottom line: In patients with myocardial infarction, LVEF >=50%, and no other indication for beta-blockers (angina, arrhythmia, heart failure), beta-blockers do not meaningfully reduce death or recurrent myocardial infarction. Additional trials that should complete in 2024 will provide additional data, including in patients with LVEF 41-49%.

Patients (n=5020 randomized)

  • Setting: Sweden (95%), Estonia, NZ, 2017-2023

  • Included:

    • Adults 1-7 days from MI

    • Obstructive coronary artery disease (CAD) on coronary angiography (i.e. stenosis >=50%, FFR <=0.8 or iFR <=0.89 in any segment)

    • Echo after MI showing left ventricular ejection fraction (LVEF) >=50% (i.e. preserved)

  • Excluded: Any other indication for beta-blockers; any contraindication to beta-blockers.

  • Baseline:

    • Age 65, 22% female

    • Median 2 days from admission to randomization

    • LVEF & coronary angiography variables not reported

    • STEMI 35%, PCI 95-96%

    • Comorbidities: Prior MI ~7%, diabetes 14%, HTN 46%, smoking ~20%

    • Medications:

      • Beta-blocker prior to admission ~11-12%

      • At discharge: ASA/P2Y12 inhibitor 95-98%, ACEI/ARB 80%, statin, 98-99%

Intervention: Beta-blocker

  • Metoprolol (1st choice; target >=100 mg/d) or bisoprolol (target >=5 mg/d)

  • 96% prescribed beta-blocker on discharge (2/3 metoprolol, 1/3 bisoprolol), ~91% receiving at “month 2” visit, 82% receiving at “1-year” visit

Comparator: No beta-blocker

  • 10% prescribed beta-blocker on discharge

Outcomes @ median 3.5 years

Primary outcome (death from any cause or new MI): Beta-blocker 7.9%, no beta-blocker 8.3% (hazard ratio [HR] 0.96, 95% confidence interval [CI] 0.79-1.16)

  • Death: 3.9% vs 4.1% (HR 0.94, 95% CI 0.71-1.24)

  • MI: 4.5% vs 4.7%

  • Bayesian re-analysis (using https://benjamin-andrew.shinyapps.io/bayesian_trials/): Assuming non-informative prior (ignoring outdated post-MI beta-blocker RCTs from the pre-reperfusion era), posterior probability=19% of an absolute risk reduction of >=1% absolute risk reduction (HR<=0.88) at 3.5 years

Safety

  • Hospitalization for bradycardia, 2-30 AVB, hypotension, syncope, or PPM implantation: 3.4% vs 3.2% (HR 1.08, 95% CI 0.79-1.46)

  • Hospitalization for asthma or COPD: 0.6% in both groups (HR 0.94, 0.46-1.89)

Internal validity

  • Randomization using permuted blocks

  • Allocation via web-based system

  • Performance bias: Moderate crossover (18% from beta-blocker to no beta-blocker by 1 year in intervention group; ~10% to beta-blocker in comparator group) biases the results toward the null

  • Detection bias: No blinding of participants or treating clinicians (open-label), but objective (death from any cause) & semi-objective outcomes (e.g. MI hospitalization) minimize risk of detection bias

  • No loss to follow-up (but missing data for 8 who emigrated, 4 withdrew consent)

  • Intention-to-treat analysis

Generalizability & other considerations

  • Who does these results NOT apply to?

    • These results do NOT apply to patients with another valid cardiovascular indication for beta-blockers, including:

      • Angina (despite PCI/CABG, if indicated)

      • Arrhythmia (ventricular arrhythmia, atrial arrhythmia requiring rate control, congenital long QT syndrome, etc)

      • Ejection fraction <50% [especially those with heart failure]

      • HF with reduced/mildly-reduced/improved LVEF

  • With that said, these results broadly apply to patients not captured within the above, which is most patients with MI seen in contemporary practice

  • This is the first contemporary trial of beta-blockers post-MI (see https://nerdcat.org/studysummaries/beta-blockers-cad for our summary of this previous evidence)

    • Prior to this trial, practice was mainly driven by a 1999 meta-analysis of RCTs conducted 1966-1991; prior to widespread use of now-established treatments for ACS/MI (especially reperfusion with PCI/fibrinolytics, ASA, statins)

  • Several other ongoing trials will shed further light on the role of beta-blockers in patients post-MI with LVEF >40%, including:

    • ABYSS (n=3700, France): Beta-blocker continuation vs discontinuation 6 months post-MI (excluding patients with LVEF <40%, persistent angina/ischemia, HF in last 2 y, arrhythmia)

    • BETAMI (n=2900, Norway) & DANBLOCK (n=2760, Denmark): Beta-blocker vs no beta-blocker post-MI (excluding patients with LVEF <40%, clinical heart failure, LV akinesia in >=3 segments, arrhythmia)

SELECT: Semaglutide in patients with CV disease & overweight/obesity

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SELECT. N Engl J Med 2023; 389:2221-2232

Bottom line: In overweight/obese patients with existing CV disease, semaglutide reduced the risk of death & cardiovascular events and reduced weight, but increased the risk of discontinuation due to GI intolerance. For every 1000 patients treated for 3.3 years, 9 deaths and 10 non-fatal MIs would be avoided, but 84 more patients receiving semaglutide would stop the drug due to GI intolerance.

Patients (n=17,604 randomized)

  • 41 countries, Oct 2018-March 2021

  • Included:

    • Age >=45 years

    • BMI >=27

    • Established cardiovascular disease: Prior MI or stroke (ischemic or hemorrhagic), or symptomatic PAD

  • Key exclusions:

    • Diabetes: Prior diagnosis, A1c >=6.5% at screening, or treatment with GLP1 RA or any other glucose-lowering drug

    • NYHA 4 HF

    • ESRD/dialysis

  • Baseline:

    • Age 62 y, male 72%

    • White 84%, Asian 8%, Black 4%

    • Weight mean 97 kg, BMI mean 33.3 (71.5% BMI >=30)

    • MI 76%, stroke 23%, symptomatic PAD 9%, HF 24%

    • EQ-5D-VAS 77/100

    • ASA 78%, P2Y12i 33-34%, statin 90%, beta-blocker 70%

Intervention: Semaglutide subcutaneous once weekly

  • Starting dose: 0.24 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)

    • 77% of those still taking the drug at year 2 received the target dose

Comparator: Matching placebo

Outcomes @ median 3.3 years

All % present semaglutide first, then placebo

  • Death: 4.3% vs 5.2%, HR 0.81 (0.71-0.93), i.e. -0.3%/y

  • Primary outcome: Composite of CV death, non-fatal MI, or non-fatal stroke:

    • 6.5% vs 8.0%, HR 0.80 (95% CI 0.72-0.90), -1.5% or ~ -0.5%/y

    • CV death: 2.5% vs 3.0%, HR 0.85 (0.71-1.01)

    • Non-fatal MI: 2.7% vs 3.7%, HR 0.72 (0.61-0.85)

    • Non-fatal stroke: 1.7% vs 1.9%, HR 0.93 (0.74-1.15)

    • Subgroup: Visually fairly consistent results across all subgroups (including sex, age, BMI, with vs without HF), though p-values for interaction by subgroup not provided

  • HF composite (CV death, HF hospitalization or urgent medical visit for HF: 3.4% vs 4.1%, HR 0.82 (0.71-0.96)

  • Renal composite (renal death, dialysis, transplantation, eGFR <15, persistent eGFR reduction >=50%, or persistent uACR >300 mg/g): 1.8% vs 2.2%, HR 0.78 (0.63-0.96)

  • Safety

    • Serious adverse events: 33.4% vs 36.4% (-3%)

    • Treatment discontinuation: 26.7% vs 23.6% (+4.1%)

    • Adverse event leading to discontinuation: 16.6% vs 8.2% (+8.4%)

    • Gallbladder-related disorder: 2.8% vs 2.3% (+0.5%)

    • Acute pancreatitis: 0.2% vs 0.3%

  • Mean difference in %change in weight at 2 years: -8.5% vs placebo

Internal validity

  • Computer-generated random sequence generation

  • Allocation concealment by centralized interactive web-based response system

  • Blinding by matching placebo & titration schedule

  • Intention-to-treat analysis

  • 2.2% lost to follow-up

Generalizability

  • All patients in this trial had some form of prior CVD, mostly atherosclerotic/ischemic disease, and were inherently at “high” risk of recurrent CV event. “Primary prevention” patients, or those with CAD or cerebrovascular disease without prior MI or stroke would inherently be at lower risk & therefore may experience lower absolute benefit.

  • Subgroup based on history of HF & HF subtype:

    • Consistent reductions in MACE & HF events regardless of history of HF (with vs without) or HF subtype (HFrEF vs HFmrEF/pEF); all p-interaction >0.10

  • Details on the subgroup of patients with HF are currently sparse, and it is unclear if this benefit extends across the spectrum of LVEF

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)