GALACTIC-HF: Omecamtiv mecarbil in patients with heart failure with reduced ejection fraction

Bottom Line:

  • In patients with symptomatic HF with reduced ejection fraction (HFrEF), omecamtiv mecarbil did not reduce the risk of death, HF hospitalizations vs placebo over a median of 22 months.

  • Omecamtiv mecarbil did reduce the primary composite outcome (CV death, HF hospitalization or worsening HF requiring urgent outpatient visit); however, this was driven by urgent outpatient visits & is of unclear clinical importance.

Patients (n=8256):

  • Included

    • Chronic HF with NYHA 2-4 & ejection fraction ≤35%

    • Age 18-85 y

    • Either

      • Inpatient: Currently hospitalized for HF

      • Outpatient: HF hospitalization or ED visit in prior year

    • Elevated natriuretic peptides

      • NT-proBNP ≥400 pg/mL if sinus rhythm or ≥1200 pg/mL if afib

      • BNP ≥125 pg/mL if sinus rhythm or ≥375 pg/mL if afib

  • Key exclusion

    • SBP <85 mm Hg or >140 mm Hg

    • eGFR <20

    • Untreated severe ventricular arrhythmia, or use of chronic antiarrhythmic therapy (except amiodarone, beta-blockers, digoxin & CCBs)

    • Certain cardiomyopathies: Severe uncorrected valvular heart disease, hypertrophic or infiltrative cardiomyopathy, active myocarditis, constrictive pericarditis, or clinically significant congenital heart disease

    • ACS, stroke, TIA or cardiac surgery/intervention within 3 months

    • Mechanical hemodynamic support or invasive mechanical ventilation in past 7 days

    • IV inotropes/vasopressors in past 3 days

    • IV diuretics or vasodilators, supplemental O2, non-invasive mechanical ventilation within 12 hours

  • Baseline characteristics

    • Age 64.5 y, 21% female, 78% white

    • 25% enrolled as inpatients, 75% enrolled as outpatients

    • NYHA 2 (53%), 34 (44%), 4 (3%)

    • KCCQ-Total Symptom Score: 69/100 (outpatients ~75, inpatients ~53)

    • LVEF 26.5%

    • MAGGIC risk score 23 (predicts a 1-year risk of death of ~13%)

    • T2DM 40%, AF 27%

    • SBP 116, HR 72, NT-proBNP ~2000, eGFR 59

    • Meds: ACEI/ARB/ARNI 87% (ARNI 20%), BB 94%, MRA 78%, SGLT2i 2.5%

    • Devices: CRT 14%, ICD 32%

Intervention: Omecamtiv mecarbil 25-50 mg BID based on therapeutic drug monitoring

  • Starting dose: 25 mg BID

  • Dose at 12 weeks: 10% discontinued or missing, 25 mg BID (29%), 37.5 mg BID (14%), 50 mg BID (48%)

Therapeutic drug monitoring protocol from final study protocol

Comparator: Matching placebo

Outcomes at median 22 months

Modest reduction in the risk of a primary outcome (time to first composite of cardiovascular death, HF hospitalization or worsening HF requiring urgent outpatient visit): 37.0% vs 39.1% (HR 0.92, 95% CI 0.86-0.99)

However, no differences in:

  • Death from any cause: Omecamtiv mecarbil 25.9% vs placebo 25.9%

    • Hazard ratio (HR) 1.00 (95% confidence interval [CI] 0.92-1.09)

  • First HF hospitalization: 27.7% vs 28.7% (HR 0.95, 95% CI 0.87-1.03)

Conflicting effect on quality of life with questionable clinical importance:

  • In outpatients, change vs placebo: -0.5 (95% CI -1.4 to +0.5)

  • In inpatients, change vs placebo: +2.5 (95% CI +0.5 to +4.5)

No increase in key safety outcomes:

  • Serious adverse events: 57.7% vs 59.4% (HR 0.97, 0.94-1.01)

  • Discontinuation due to adverse events: 9.0% vs 9.3% (HR 0.97, 95% CI 0.85-1.11)

  • Major cardiac ischemic events: 4.9% vs 4.6% (HR 1.06, 95% CI 0.87-1.29)

  • Ventricular tachyarrhythmia: 7.1% vs 7.4% (HR 0.95, 95% CI 0.82-1.11)

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

  • Computer-generated randomization, stratified by setting (inpatient or outpatient)

  • Allocation concealed by interactive voice/web-response system

  • Participants, clinicians unaware of treatment assignment & drug plasma concentrations (blinded)

  • Loss-to-follow-up 2.1% (unknown vital status or died with incomplete follow-up on non-fatal events)

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

Other considerations

Are the results clinically important?

  • Although administered on top of standard of care, the ~8% relative risk reduction of the primary outcome in this trial is quite modest, especially compared with other interventions for HFrEF

    • In addition to the uncertain clinical importance of the primary outcome, it is important to note that omecamtiv mecarbil did not reduce the risk of dying, nor did it have a clear effect on HF hospitalizations.

    • Thus, the main driver of the difference in the primary outcome was worsening HF requiring an urgent outpatient visit, which is far less important than the other 2 components

Generalizability

  • Overall, the participants of this trial represent a sicker population of HFrEF patients at very high risk of death & hospitalizations, as reflected in the high event rates

  • Additionally, only a minority of GALACTIC-HF were treated with contemporary HFrEF drugs (ARNI & SGLT2i)

  • Therefore, the absolute benefits for patients who have less severe HFrEF &/or greater use of ARNIs & SGLT2i are likely to be even smaller

Practical considerations

  • Cost: Unknown as not yet marketed in Canada/US (as of Dec 29, 2020)

  • Routine:

    • Dosing: Requires twice-daily administration.

    • Monitoring: Requires therapeutic drug monitoring at least once to tailor dose for efficacy & safety - longer term requirements unknown. Does not require any electrolyte/renal monitoring.

SOLOIST-WHF: Sotagliflozin in patients with diabetes and recent worsening heart failure

Bhatt DL, et al. Sotagliflozin in patients with diabetes and recent worsening heart failure. NEJM 2020

Bottom line:

  • Among patients with type 2 diabetes who were within 3 days of discharge from an acute HF admission (any ejection fraction), sotagliflozin (combined SGLT1+SLGTI2 inhibitor) reduced the risk of a composite of CV death, HF hospitalization or urgent visit for HF requiring IV diuretics vs placebo (NNT 7) at 9 months.

  • These results are consistent with & extend those of the DAPA-HF and EMPEROR-Reduced trials in patients with HFrEF +/- diabetes, as well as CANVAS, DECLARE and EMPA-REG in patients with type 2 diabetes +/- HF.

  • Sotagliflozin increased the risk of diarrhea (by 3%) and severe hypoglycemia (by 1%), which may be unique to this agent due to its effect on SGLT1.

Patients (n=1222)

  • From June 2019-March 2020, 1549 screened -> 1222 randomized

  • Included

    • Acute HF (before discharge or within 3 after discharge)

      • Hospitalization or urgent visit to emergency department, HF unit, or infusion center for worsening HF

      • Treated with IV loop diuretics during hospitalization/urgent visit

      • BNP 150+ pg/mL (450+ if AF) or NT-proBNP 600+ (1800+ if AF)

      • HF diagnosis for 3+ months

      • Prior chronic treatment with loop diuretic 30+ days

    • Clinically stable (no need for supplemental O2, SBP 100+ mm Hg, no IV inotropes/vasodilators, transitioned from IV to PO diuretics)

    • Type 2 diabetes (existing diagnosis prior to HF admission or lab diagnosis during admission)

    • No ejection fraction restriction

  • Key exclusion criteria:

    • Age <18 or >85

    • Acute HF triggered by PE, CVA or MI, or not caused primarily by volume overload (e.g. infection, arrhythmia, severe anemia)

    • Specific HF etiologies (HOCM, peripartium cardiomyopathy, uncorrected primary valvular disease, uncorrected thyroid disorder)

    • eGFR <30

  • Baseline (average/proportions)

    • 70 y/o, female 34%

    • White 93%, Black 4%, Asian 1%

    • North America ~7%

    • HF characteristics

      • Median KCCQ-12 35/100

      • Median LVEF 35% (LVEF<50% in 79%)

      • Median NT-proBNP ~1800

    • Clinical variables: SBP 122, eGFR 50, HbA1c 7.1%

    • Therapies

      • ACEI 42%, ARB 40%, ARNI 15%

      • Beta-blocker 92%

      • MRA ~65%

      • Antihyperglycemics: Metformin 53%, sulfonylurea (19%,, DPP4i 16%, GLP1RA 3%, insulin 36%

Intervention & Control

  • Intervention: Sotagliflozin

    • Starting dose: 200 mg once daily (median time from discharge to first dose: 2 days)

    • Uptitrated to 400 mg once daily as tolerated after 2 weeks

  • Control: Matching placebo

Outcomes

CV outcomes @ median 9 months

  • Death from any cause: Sotagliflozin 13.5% vs placebo 16.3% (HR 0.82, 0.59-1.14)

  • Composite of time to first CV death or HF hospitalization:

    • Sotagliflozin 33% vs placebo 48% (15% absolute reduction, number needed to treat [NNT]=7

    • Hazard ratio (HR) 0.71 (95% confidence interval 0.56-0.89)

  • Primary outcome (total number of CV death, HF hospitalization, or urgent visit for HF resulting in IV therapy): 51.0 vs 76.3 /100 patient-years (difference 25.3 events/100 patient-years)

    • Consistent across subgroups, including by LVEF (LVEF <50%: HR 0.72 [95% CI 0.56-0.94] & LVEF >=50%: HR 0.48 [95% CI 0.27-0.86]

Quality of life (QoL) @ month 4

  • Measured using short-form Kansas City Cardiomyopathy Questionnaire [KCCQ-12], range from 0 [worst] to 100 [best], Minimal clinically-important difference is a 5-point improvement/worsening)

  • Mean difference between groups: +4.1 points (/100) in favor of sotagliflozin

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

  • Significant increases in:

    • Diarrhea: 6.1% vs 3.4%

    • Severe hypoglycemia: 1.5% vs 0.3%

  • No significant differences in:

    • Serious adverse events leading to study drug discontinuation: 3.0% vs 2.8%

    • Discontinuation study drug: 13.0% vs 15.3%

    • Hypotension: 6.0% vs 4.6%

    • Acute kidney injury: 4.1% vs 4.4%

    • UTI: 4.8% vs 5.1%

    • Hyperkalemia: 4.3% vs 5.1%

    • Diabetic ketoacidosis: 0.3% vs 0.7%

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

  • Computer-generated randomization, stratified by LVEF (<50% or >=50%)

  • Allocation concealed by interactive voice/web-response system

  • Participants, clinicians unaware of treatment assignment (blinded)

  • Loss-to-follow-up 3.5% (similar between groups)

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

Search for study summaries based on condition or drug class

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

in

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.

SGLT2i HF mortality.png

  • 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

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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

Indirect comparison of relative efficacy of different HFrEF pharmacotherapeutic options